CN115925597A - Preparation method of bis (4-sulfophenyl) disulfide - Google Patents
Preparation method of bis (4-sulfophenyl) disulfide Download PDFInfo
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- CN115925597A CN115925597A CN202211644243.XA CN202211644243A CN115925597A CN 115925597 A CN115925597 A CN 115925597A CN 202211644243 A CN202211644243 A CN 202211644243A CN 115925597 A CN115925597 A CN 115925597A
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- 238000002360 preparation method Methods 0.000 title claims description 5
- LUENVHHLGFLMFJ-UHFFFAOYSA-N 4-[(4-sulfophenyl)disulfanyl]benzenesulfonic acid Chemical compound C1=CC(S(=O)(=O)O)=CC=C1SSC1=CC=C(S(O)(=O)=O)C=C1 LUENVHHLGFLMFJ-UHFFFAOYSA-N 0.000 title abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 131
- 238000000034 method Methods 0.000 claims abstract description 43
- 230000001590 oxidative effect Effects 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 75
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 230000008569 process Effects 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 238000005580 one pot reaction Methods 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 claims description 4
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 239000012954 diazonium Substances 0.000 claims description 2
- -1 diazonium salt compound Chemical class 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- JCBJVAJGLKENNC-UHFFFAOYSA-M potassium ethyl xanthate Chemical compound [K+].CCOC([S-])=S JCBJVAJGLKENNC-UHFFFAOYSA-M 0.000 description 10
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 235000010288 sodium nitrite Nutrition 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 238000001514 detection method Methods 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 3
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 235000009518 sodium iodide Nutrition 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- LBJNMUFDOHXDFG-UHFFFAOYSA-N copper;hydrate Chemical compound O.[Cu].[Cu] LBJNMUFDOHXDFG-UHFFFAOYSA-N 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a novel method for synthesizing a compound shown in a formula 1. The method comprises the following steps: obtaining a compound shown as a formula 3 by using the compound shown as the formula 2; reacting a compound shown as a formula 3 with a compound shown as a formula 4 to generate a compound shown as a formula 5; reacting the compound shown in the formula 5 to generate a compound shown in a formula 6; and oxidizing the compound shown in the formula 6 to generate the compound shown in the formula 1. The method of the invention can prepare bis (4-sulfophenyl) disulfide safely, with high yield, low cost and high efficiency.
Description
Technical Field
The invention relates to the fields of medicine and fine chemistry. In particular, the present invention relates to a process for the preparation of bis (4-sulfophenyl) disulfide.
Background
The bis (4-sulfophenyl) disulfide is a functional compound used for synthesizing fluorine-containing reagents and new drug intermediates. Therefore, the art has been studied for the synthesis of bis (4-sulfophenyl) disulfide. For example, chinese patent application CN101386589A reports a synthesis method of bis (4-sulfophenyl) disulfide (formula 1), and the specific synthetic route is shown as the following formula:
according to the method, benzenesulfonic acid is used as a starting material, and is subjected to para-position substitution reaction with chlorosulfonic acid to obtain a compound shown in a formula 7, then a compound shown in a formula 6 is obtained through reduction reaction, and the compound shown in the formula 6 is oxidized by DMSO to obtain a compound shown in a formula 1. The yield of the compound of formula 6 obtained by the first step of substitution reaction and the second step of reduction reaction is 63%, and the yield of the compound of formula 1 obtained by the third step of oxidation of the compound of formula 6 by DMSO is only 29%. And the method utilizes a dangerous reagent chlorosulfonic acid, so the production danger is high.
For another example, WO2003043985 also reports a method for synthesizing the compound of formula 1. The specific synthetic route is shown as the following formula:
the method uses highly toxic thiophenol as a starting material to generate a compound shown in a formula 8 through an oxidation reaction, and the compound shown in the formula 8 is subjected to a substitution reaction with chlorosulfonic acid to generate a compound shown in a formula 1. Although the synthetic route of the method is short, the method uses highly toxic raw materials, has high cost and is difficult to realize industrial production.
Therefore, there is a need in the art for a novel method for synthesizing bis (4-sulfophenyl) disulfide, which has the advantages of safety, low cost, high yield, etc.
Disclosure of Invention
The present invention aims to provide a novel method for synthesizing bis (4-sulfophenyl) disulfide, thereby producing bis (4-sulfophenyl) disulfide safely at low cost and in high yield.
In a first aspect, the present invention provides a process for preparing a compound of formula 1, said process being represented by the following reaction scheme:
the method comprises the following steps:
1) Carrying out a reaction on the compound shown in the formula 2 to generate a diazonium salt compound shown in a formula 3;
2) Reacting the compound shown in the formula 3 obtained in the step 1) with a compound shown in a formula 4 to generate a compound shown in a formula 5;
3) Reacting the compound shown in the formula 5 obtained in the step 2) to generate a compound shown in a formula 6; and
4) Oxidizing the compound shown as the formula 6 obtained in the step 3) to generate the compound shown as the formula 1.
In a specific embodiment, in step 2), the compound of formula 3 is reacted with the compound of formula 4 at a temperature T1 to produce a compound of formula 5;
the temperature T1 is 5-70 ℃; preferably 35-70 ℃; more preferably from 65 ℃ to 70 ℃.
In specific embodiments, the molar ratio of the compound represented by formula 2 to the compound represented by formula 4 is 1 to 1; preferably 1; more preferably 1.
In a specific embodiment, in the step 3), the compound shown in the formula 5 is reacted under the action of a base B1 to generate a compound shown in a formula 6;
the alkaline agent B1 is sodium hydroxide, potassium hydroxide, cesium hydroxide or a mixture thereof; potassium hydroxide is preferred.
In a specific embodiment, in step 3), the compound represented by formula 5 is reacted at a temperature T2 to produce a compound represented by formula 6;
the temperature T2 is 20-75 ℃; preferably 45 ℃ to 75 ℃; more preferably 70 ℃ to 75 ℃.
In a specific embodiment, in step 4), the compound represented by formula 6 is oxidized at a temperature T3 to produce a compound represented by formula 1;
the temperature T3 is 0-50 ℃; preferably 45 ℃ to 75 ℃; more preferably 70 ℃ to 75 ℃.
In a specific embodiment, in step 4), the compound represented by formula 6 is oxidized in a solvent S1 to produce a compound represented by formula 1;
the solvent S1 is selected from methanol, isopropanol, acetonitrile or a mixture thereof; acetonitrile is preferred.
In a specific embodiment, the steps 1) to 3) are carried out in a one-pot method.
In a specific embodiment, the yield of the compound shown in the formula 6 obtained in the steps 1) to 3) is higher than 70%; preferably higher than 80%; more preferably higher than 90%.
In a specific embodiment, the yield of the compound shown in the formula 1 obtained in the step 4) is higher than 80%; preferably higher than 85%; more preferably higher than 90%.
In a preferred embodiment, the total yield of the compound of formula 1 synthesized by the method of the present invention starting from the compound of formula 2 is higher than 75%; preferably higher than 80%; more preferably higher than 85%.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The present inventors have made extensive and intensive studies and have unexpectedly found a process for producing bis (4-sulfophenyl) disulfide from inexpensive starting materials, which enables the production of bis (4-sulfophenyl) disulfide safely and inexpensively in high yield. The present invention has been completed based on this finding.
Method of the invention
In order to overcome the defects in the method for preparing bis (4-sulfophenyl) disulfide in the prior art, the inventor provides a synthesis method of the compound shown in the formula 1, which is safe and beneficial to industrial production, by taking the compound shown in the formula 2 which is easily available in the market as a starting material. The reaction formula of the synthetic route is shown as follows:
in the method of the invention, the compound shown in formula 2 is firstly reacted to generate the compound shown in formula 3, then the compound shown in formula 3 is reacted with the compound shown in formula 4 to generate the compound shown in formula 5, the compound shown in formula 5 is reacted to generate the compound shown in formula 6 under alkaline conditions, and finally the compound shown in formula 6 is subjected to oxidation reaction to obtain the final compound shown in formula 1.
In the method, the compound shown in the formula 2 to the compound shown in the formula 6 can be obtained by adopting a one-pot method, and the yield is about 93 percent; and the compound represented by formula 6 gives the compound represented by formula 1 in a yield of 92%.
On the basis of the reaction process, the invention also optimizes the reaction process conditions, thereby obviously improving the reaction yield.
In a specific embodiment, the compound of formula 3 is reacted with the compound of formula 4 to produce the compound of formula 5, preferably at a temperature of 5 ℃ to 70 ℃; preferably 35 to 70 ℃; more preferably from 65 ℃ to 70 ℃.
In a specific embodiment, to produce the compound represented by formula 5, the molar ratio of the compound represented by formula 2 to the compound represented by formula 4 is preferably 1; preferably 1; more preferably 1.
In a specific embodiment, the compound of formula 5 is reacted with a base, including but not limited to sodium hydroxide, potassium hydroxide, cesium hydroxide, or mixtures thereof, preferably potassium hydroxide, to produce a compound of formula 6; the compound of formula 5 is preferably reacted at a temperature of from 20 ℃ to 75 ℃, preferably from 45 ℃ to 75 ℃, more preferably from 70 ℃ to 75 ℃ to produce a compound of formula 6.
In a particular embodiment, the compound of formula 6 is preferably formed into the compound of formula 1 in a solvent, including but not limited to methanol, isopropanol, acetonitrile or mixtures thereof, preferably acetonitrile, at a temperature of from 0 ℃ to 50 ℃, preferably from 45 ℃ to 75 ℃, more preferably from 70 ℃ to 75 ℃.
In a preferred embodiment, the obtaining of the compound of formula 6 from the compound of formula 2 may be performed in a "one-pot" process, giving a yield of the compound of formula 6 of more than 70%, preferably more than 80%, more preferably more than 90%.
In a preferred embodiment, the yield of the compound of formula 1 from the compound of formula 6 using the process of the present invention is greater than 80%; preferably higher than 85%; more preferably higher than 90%.
In a preferred embodiment, the total yield of the compound of formula 1 synthesized by the method of the present invention starting from the compound of formula 2 is higher than 75%; preferably higher than 80%; more preferably higher than 85%.
The invention has the advantages that:
1. the present invention provides a novel process for the preparation of bis (4-sulfophenyl) disulfide;
2. in the method, the compound shown in the formula 6 obtained by reacting the compound shown in the formula 2 can be obtained by a one-pot method with high yield;
3. the method of the invention uses cheap and easily available potassium ethyl xanthate as a thioreagent to construct sulfydryl;
4. the method has high reaction yield and mild reaction conditions, thereby being beneficial to industrial production.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
Example 1: synthesis of Compounds of formula 6
Taking three reaction bottles, respectively adding 121.2 g (0.7 mol) of the compound of formula 2, then adding 750 ml of water and 48.3 g (0.7 mol) of sodium nitrite, after the addition is finished and the temperature is reduced to 0-5 ℃, dropwise adding 150 ml of concentrated hydrochloric acid at controlled temperature, reacting for 30min, and adding 112 g (0.7 mol) of potassium ethylxanthate aqueous solution into the reaction bottle No. 1 at the reaction temperature of 50-55 ℃; no. 2 reaction bottle, controlling the reaction temperature at 50-55 ℃, adding 224 g (1.4 mol) of potassium ethylxanthate aqueous solution; a No. 3 reaction bottle is added with 336 g (2.1 mol) of potassium ethylxanthate aqueous solution at the reaction temperature of 50-55 ℃; after the addition, TLC/HPLC detection reaction is completed, no. 1, no. 2 and No. 3 reactions are controlled to 70-75 ℃, 440 g of 30% sodium hydroxide solution is added dropwise, the temperature is controlled for reaction for 2 hours, the temperature is reduced to 0-5 ℃, and the compound of the formula 6 is obtained by filtration, the yield of the three reactions is calculated, and the yield is shown in the following table 1
TABLE 1
Example 2: synthesis of Compounds of formula 6
Taking three reaction bottles, respectively adding 121.2 g (0.7 mol) of the compound of formula 2, then adding 750 ml of water and 48.3 g (0.7 mol) of sodium nitrite, after the addition is finished and the temperature is reduced to 0-5 ℃, dropwise adding 150 ml of concentrated hydrochloric acid at controlled temperature, after reacting for 30min, adding 224 g (1.4 mol) of potassium ethylxanthate aqueous solution into No. 1 reaction bottle at the controlled reaction temperature of 5-10 ℃; no. 2 reaction bottle, controlling the reaction temperature at 30-35 ℃, adding 224 g (1.4 mol) of potassium ethylxanthate aqueous solution; a No. 3 reaction bottle is controlled to have the reaction temperature of 65-70 ℃, and 224 g (1.4 mol) of aqueous solution of potassium ethylxanthate is added; after the completion of the addition, TLC/HPLC detection reaction is completed, 440 g of 30% sodium hydroxide solution is added dropwise at 70-75 ℃ in the reaction No. 1,2,3, the temperature is controlled for reaction for 2 hours, the temperature is reduced to 0-5 ℃, and the compound of the formula 6 is obtained by filtration, and the yield of three reactions is calculated as shown in the following Table 2:
TABLE 2
Example 3: synthesis of Compounds of formula 6
Taking three reaction bottles, respectively adding 121.2 g (0.7 mol) of the compound of formula 2, then adding 750 ml of water and 48.3 g (0.7 mol) of sodium nitrite, after the addition is finished and the temperature is reduced to 0-5 ℃, dropwise adding 150 ml of concentrated hydrochloric acid at controlled temperature, reacting for 30min, and adding 224 g (1.4 mol) of aqueous solution of potassium ethylxanthate into the reaction bottles at the reaction temperature of 65-70 ℃; after the addition is finished, detecting by TLC/HPLC, and after the reaction is finished, adding 440 g of 30% sodium hydroxide solution dropwise into a No. 1 reaction bottle at the temperature of 20-25 ℃; no. 2 reaction bottle is added with 440 g of 30 percent sodium hydroxide solution dropwise at the reaction temperature of 45-50 ℃; the No. 3 reaction bottle is added with 440 g of 30 percent sodium hydroxide solution dropwise at the reaction temperature of 70-75 ℃; the temperature of the three reactions was controlled for 2 hours and the reaction was cooled to 0-5 ℃ and filtered to obtain the compound of formula 6, and the yields of the three reactions were calculated as shown in table 3 below:
TABLE 3
Example 4: synthesis of Compounds of formula 6
Taking three reaction bottles, respectively adding 121.2 g (0.7 mol) of the compound of formula 2, then adding 750 ml of water and 48.3 g (0.7 mol) of sodium nitrite, after the addition is finished and the temperature is reduced to 0-5 ℃, dropwise adding 150 ml of concentrated hydrochloric acid at controlled temperature, reacting for 30min, and adding 224 g (1.4 mol) of aqueous solution of potassium ethylxanthate into the reaction bottles at the reaction temperature of 65-70 ℃; after the addition is finished, detecting by TLC/HPLC, and after the reaction is finished, adding 440 g of 30% sodium hydroxide solution dropwise into a No. 1 reaction bottle at the temperature of 70-75 ℃; no. 2 reaction bottle is added with 616 g of 30 percent potassium hydroxide solution dropwise at the reaction temperature of 70-75 ℃; the No. 3 reaction bottle is added with 1500 g of 30 percent cesium hydroxide solution by dripping at the temperature of 70 to 75 ℃; the temperature of the three reactions was controlled for 2 hours and the reaction was cooled to 0-5 ℃ and filtered to obtain the compound of formula 6, and the yields of the three reactions were calculated as shown in table 4 below:
TABLE 4
Example 5: synthesis of Compounds of formula 6
242.4 g (1.4 mol) of the compound of the formula 2 is added into a reaction bottle, then 750 ml of water and 96.6 g (1.4 mol) of sodium nitrite are added, after the addition is finished and the temperature is reduced to 0-5 ℃, 300 ml of concentrated hydrochloric acid is dropwise added at controlled temperature, after the reaction is carried out for 30min, 448 g (2.8 mol) of potassium ethylxanthate aqueous solution is added at the reaction temperature of 65-70 ℃, the reaction is finished by TLC/HPLC detection, 30% of potassium hydroxide solution 616 g is dropwise added at the temperature of 70-75 ℃, the reaction is carried out for 2 h, the temperature is reduced to 0-5 ℃, and the compound of the formula 6 is obtained by filtration, 248.4 g of the compound of the formula 6, and the yield is 93.4%.
Example 6: synthesis of Compound of formula 1
Taking three reaction bottles, respectively adding 95 g (0.5 mol) of the compound of formula 6, 50 g of 30% hydrogen peroxide and 10 g of sodium iodide, and then adding 750 ml of methanol into a No. 1 reaction bottle; adding 750 ml of isopropanol into a No. 2 reaction bottle; 750 ml of acetonitrile is added into a No. 3 reaction bottle; after the addition, the temperature of the three groups of reactions is controlled to 30-35 ℃ for 4 hours, the reaction is detected by TLC, then the filtration is carried out, and the filter cake is dried to obtain the light yellow compound shown in the formula 1. The yields of the three reactions were calculated as shown in table 5 below:
TABLE 5
Example 7: synthesis of Compounds of formula 1
Taking three reaction bottles, respectively adding 95 g (0.5 mol) of the compound of formula 6, 750 ml of acetonitrile, 50 g of 30% hydrogen peroxide and 10 g of sodium iodide, and then carrying out No. 1 reaction at the temperature of 0-10 ℃ for 4 hours; the temperature of No. 2 reaction is controlled between 10 and 20 ℃ for 4 hours; the reaction No. 3 is carried out for 4 hours at the temperature of 40-50 ℃. And (4) detecting by TLC, filtering after the three groups of reactions are finished, and drying a filter cake to obtain a light yellow compound shown in the formula 1. The yields of the three reactions were calculated as shown in table 6 below:
TABLE 6
Example 8: synthesis of Compound of formula 1
190 g (1 mol) of the compound of formula 6, 1.5L acetonitrile, 100 g of 30% hydrogen peroxide and 20 g of sodium iodide are added into a reaction bottle, and then the mixture reacts for 4 hours at 20-25 ℃, and after the TLC detection reaction, the mixture is filtered, and a filter cake is dried to obtain 174.0 g of the compound of formula 1 in light yellow. The yield thereof was found to be 92.1%.
All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (10)
1. A process for the preparation of a compound of formula 1, said process being represented by the following reaction scheme:
the method comprises the following steps:
1) Carrying out a reaction on the compound shown in the formula 2 to generate a diazonium salt compound shown in a formula 3;
2) Reacting the compound shown in the formula 3 obtained in the step 1) with a compound shown in a formula 4 to generate a compound shown in a formula 5;
3) Reacting the compound shown in the formula 5 obtained in the step 2) to generate a compound shown in a formula 6; and
4) Oxidizing the compound shown as the formula 6 obtained in the step 3) to generate the compound shown as the formula 1.
2. The method of claim 1, wherein in step 2), the compound of formula 3 is reacted with the compound of formula 4 at a temperature T1 to produce the compound of formula 5;
the temperature T1 is 5-70 ℃; preferably 35 to 70 ℃; more preferably from 65 ℃ to 70 ℃.
3. The method according to claim 1, wherein the molar ratio of the compound represented by formula 2 to the compound represented by formula 4 is 1 to 1; preferably 1; more preferably 1.
4. The method as claimed in claim 1, wherein in step 3), the compound represented by formula 5 is reacted under the action of a base B1 to produce a compound represented by formula 6;
the alkaline agent B1 is sodium hydroxide, potassium hydroxide, cesium hydroxide or a mixture thereof; potassium hydroxide is preferred.
5. The method according to claim 1, wherein in step 3), the compound of formula 5 is reacted at a temperature T2 to form a compound of formula 6;
the temperature T2 is 20-75 ℃; preferably 45 ℃ to 75 ℃; more preferably 70 ℃ to 75 ℃.
6. The method of claim 1, wherein in step 4), the compound of formula 6 is oxidized at a temperature T3 to form the compound of formula 1;
the temperature T3 is 0-50 ℃; preferably 45 ℃ to 75 ℃; more preferably 70 ℃ to 75 ℃.
7. The method according to claim 1, wherein in step 4), the compound represented by formula 6 is oxidized in a solvent S1 to produce a compound represented by formula 1;
the solvent S1 is selected from methanol, isopropanol, acetonitrile or a mixture thereof; acetonitrile is preferred.
8. The method according to any one of claims 1 to 7, wherein the steps 1) to 3) are carried out in a "one-pot" process.
9. The method of any one of claims 1-7, wherein the yield of the compound of formula 6 from step 1) to step 3) is greater than 70%; preferably higher than 80%; more preferably higher than 90%.
10. The method of any one of claims 1-7, wherein step 4) provides a yield of the compound of formula 1 of greater than 80%; preferably higher than 85%; more preferably higher than 90%.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH02221254A (en) * | 1989-02-23 | 1990-09-04 | Nissan Chem Ind Ltd | Bis-(4-fluoro-2-chlorophenyl) disulfide derivative |
| CN1443180A (en) * | 2000-05-22 | 2003-09-17 | 雷迪实验室有限公司 | Novel compounds having antiinflamatory activity process for their preparation and pharmaceutical compositions containing them |
| CN1537088A (en) * | 2000-12-01 | 2004-10-13 | Transfer hydrogenation process and catalyst | |
| CN101386589A (en) * | 2008-10-22 | 2009-03-18 | 成都福瑞生物工程有限公司 | Aryl sulfur fluoride type fluorination reagent and preparation method thereof |
| CN104003918A (en) * | 2011-09-23 | 2014-08-27 | 中南大学 | Diaryl thioether compound, preparation method and antitumor application thereof |
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2022
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| JPH02221254A (en) * | 1989-02-23 | 1990-09-04 | Nissan Chem Ind Ltd | Bis-(4-fluoro-2-chlorophenyl) disulfide derivative |
| CN1443180A (en) * | 2000-05-22 | 2003-09-17 | 雷迪实验室有限公司 | Novel compounds having antiinflamatory activity process for their preparation and pharmaceutical compositions containing them |
| CN1537088A (en) * | 2000-12-01 | 2004-10-13 | Transfer hydrogenation process and catalyst | |
| CN101386589A (en) * | 2008-10-22 | 2009-03-18 | 成都福瑞生物工程有限公司 | Aryl sulfur fluoride type fluorination reagent and preparation method thereof |
| CN104003918A (en) * | 2011-09-23 | 2014-08-27 | 中南大学 | Diaryl thioether compound, preparation method and antitumor application thereof |
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