CN104311456A - Preparation method of guaiacol potassium sulfoacid - Google Patents
Preparation method of guaiacol potassium sulfoacid Download PDFInfo
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- CN104311456A CN104311456A CN201410531751.6A CN201410531751A CN104311456A CN 104311456 A CN104311456 A CN 104311456A CN 201410531751 A CN201410531751 A CN 201410531751A CN 104311456 A CN104311456 A CN 104311456A
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- thiocol
- hydroxyacetanilide
- hydroxy
- reaction
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- WTLYFCZMLRAPLI-UHFFFAOYSA-N 2-methoxyphenol;potassium Chemical compound [K].COC1=CC=CC=C1O WTLYFCZMLRAPLI-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- ADVGKWPZRIDURE-UHFFFAOYSA-N 2'-Hydroxyacetanilide Chemical compound CC(=O)NC1=CC=CC=C1O ADVGKWPZRIDURE-UHFFFAOYSA-N 0.000 claims abstract description 34
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Chemical compound O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 claims abstract description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 24
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims abstract description 21
- 238000006277 sulfonation reaction Methods 0.000 claims abstract description 18
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims abstract description 14
- 239000002994 raw material Substances 0.000 claims abstract description 12
- 239000003960 organic solvent Substances 0.000 claims abstract description 11
- 238000006193 diazotization reaction Methods 0.000 claims abstract description 9
- 239000012954 diazonium Substances 0.000 claims abstract description 8
- 150000001989 diazonium salts Chemical class 0.000 claims abstract description 8
- 238000006198 methoxylation reaction Methods 0.000 claims abstract description 7
- FZERHIULMFGESH-UHFFFAOYSA-N methylenecarboxanilide Natural products CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 claims abstract description 7
- 230000007062 hydrolysis Effects 0.000 claims abstract description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 5
- 229960001413 acetanilide Drugs 0.000 claims abstract description 4
- LULCPJWUGUVEFU-UHFFFAOYSA-N Phthiocol Natural products C1=CC=C2C(=O)C(C)=C(O)C(=O)C2=C1 LULCPJWUGUVEFU-UHFFFAOYSA-N 0.000 claims description 20
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 claims description 16
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 14
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 9
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 4
- ODFJOVXVLFUVNQ-UHFFFAOYSA-N acetarsol Chemical compound CC(=O)NC1=CC([As](O)(O)=O)=CC=C1O ODFJOVXVLFUVNQ-UHFFFAOYSA-N 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 21
- 239000001103 potassium chloride Substances 0.000 abstract description 5
- 235000011164 potassium chloride Nutrition 0.000 abstract description 5
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- QDRCGSIKAHSALR-UHFFFAOYSA-N 4-hydroxy-3-methoxybenzene-1-sulfonic acid Chemical compound COC1=CC(S(O)(=O)=O)=CC=C1O QDRCGSIKAHSALR-UHFFFAOYSA-N 0.000 abstract 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 abstract 1
- 230000002378 acidificating effect Effects 0.000 abstract 1
- 229940092714 benzenesulfonic acid Drugs 0.000 abstract 1
- 238000012805 post-processing Methods 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- 239000000047 product Substances 0.000 description 14
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- 235000010288 sodium nitrite Nutrition 0.000 description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 4
- 238000007689 inspection Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- RSAIREHPJZNTTI-UHFFFAOYSA-N [K].OC=1C=C(C=CC1OC)S(=O)(=O)O Chemical compound [K].OC=1C=C(C=CC1OC)S(=O)(=O)O RSAIREHPJZNTTI-UHFFFAOYSA-N 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 206010036790 Productive cough Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- GNTDGMZSJNCJKK-UHFFFAOYSA-N divanadium pentaoxide Chemical compound O=[V](=O)O[V](=O)=O GNTDGMZSJNCJKK-UHFFFAOYSA-N 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229960001867 guaiacol Drugs 0.000 description 2
- LHGVFZTZFXWLCP-UHFFFAOYSA-N guaiacol Chemical compound COC1=CC=CC=C1O LHGVFZTZFXWLCP-UHFFFAOYSA-N 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 239000000043 antiallergic agent Substances 0.000 description 1
- 229910052785 arsenic Inorganic materials 0.000 description 1
- RQNWIZPPADIBDY-UHFFFAOYSA-N arsenic atom Chemical compound [As] RQNWIZPPADIBDY-UHFFFAOYSA-N 0.000 description 1
- 239000003637 basic solution Substances 0.000 description 1
- 229910052797 bismuth Inorganic materials 0.000 description 1
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052793 cadmium Inorganic materials 0.000 description 1
- BDOSMKKIYDKNTQ-UHFFFAOYSA-N cadmium atom Chemical compound [Cd] BDOSMKKIYDKNTQ-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003172 expectorant agent Substances 0.000 description 1
- 230000003419 expectorant effect Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000000762 glandular Effects 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000000413 hydrolysate Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- -1 methoxyl group Chemical group 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- QFRKWSPTCBGLSU-UHFFFAOYSA-M potassium 4-hydroxy-3-methoxybenzene-1-sulfonate Chemical group [K+].COC1=CC(S([O-])(=O)=O)=CC=C1O QFRKWSPTCBGLSU-UHFFFAOYSA-M 0.000 description 1
- QEAJOOURKCKFSV-UHFFFAOYSA-M potassium;3-hydroxy-4-methoxybenzenesulfonate Chemical compound [K+].COC1=CC=C(S([O-])(=O)=O)C=C1O QEAJOOURKCKFSV-UHFFFAOYSA-M 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 229910052814 silicon oxide Inorganic materials 0.000 description 1
- 230000002557 soporific effect Effects 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- XTHPWXDJESJLNJ-UHFFFAOYSA-N sulfurochloridic acid Chemical compound OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of guaiacol potassium sulfoacid. The preparation method comprises the following steps of A, carrying out sulfonation reaction on a raw material 2-hydroxyacetanilide shown in a structural formula (I) and sulfur trioxide dissolved in an organic solvent so as to prepare 2-hydroxy-5-sulfo acetanilide, and concentrating; B, carrying out acetamido hydrolysis and diazotization under acidic condition; C, carrying out methoxylation reaction on the obtained diazonium salt and a methanol solution containing potassium hydroxide so as to obtain 3-methoxy-4-hydroxy benzenesulfonic acid shown in a structural formula (II); and D, then separating and purifying in a potassium chloride solution, so as to prepare the target product 4-hydroxy-3-methoxy potassium benzenesulfonic acid shown in a structural formula (III), wherein the purity reaches over 99%. The raw materials are cheap and are easy available, the reaction conditions are mild, the product has a single structure, the postprocessing is simple, and the preparation method is suitable for large scale production.
Description
Technical field
The present invention relates to a kind of new synthetic method of thiocol, particularly the synthetic method of highly purified contraposition thiocol, belongs to pharmaceutical chemistry technical field.
Background technology
Thiocol is powerful expectorant, and respiratory tract glandular secretion is increased, and sputum is diluted, and is easy to expectoration; Anticholinergic drug can be strengthened as atropinic effect; With calmness, soporific, anti-allergy agent also with increasing the restraining effect of this product to maincenter.The thiocol finished product of current commercial type is usually the mixture of 4-hydroxy 3-methoxybenzene potassium sulfonate and 3-hydroxyl-4-methoxy benzenesulfonic acid potassium (English name is potassium 4-hydroxy-3-methoxybenzene-sulphonate/potassium 3-hydroxy-4-methoxybenzenesulphonate).2014, Chinese thiocol compound medicine sales volume reached 5MG, comparatively within 2013, increased by 25%.5 years (2009-2014) increases by 30% every year in the past.The market demand potential is very large.
The method of current synthesizing guaiacol potassium sulfonate is mainly carried out sulfonation by methyl catechol (hydroxyanisole) and derivative thereof and is obtained.The mixture of products therefrom mainly 4-hydroxy 3-methoxybenzene potassium sulfonate and 3-hydroxyl-4-methoxy benzenesulfonic acid potassium, roughly the ratio of 4-hydroxy 3-methoxybenzene potassium sulfonate and 3-hydroxyl-4-methoxy benzenesulfonic acid potassium is 70%: 30%.The product only having Japan to produce can reach 4-hydroxy 3-methoxybenzene potassium sulfonate more than 98%.Because the drug effect of the mixture of two kinds of isomer of thiocol is relatively poor, therefore, development research highly purified 4-hydroxy 3-methoxybenzene potassium sulfonate product has wide market outlook.
Sulfonation reaction is traditional conventional organic chemical reactions, is that sulphonating agent is directly with the reaction that sulfonic group replacement hydrogen atom carries out.The mixture of sulphur trioxide, chlorsulfonic acid, sulfurous gas and chlorine in the different solvents such as conventional sulphonating agent has the vitriol oil, is dissolved in hydrochloric ether, sulfur dioxide liquid, dioxane and pyridine and sulfuryl chloride etc.Sulfuric acid is a kind of relatively mild sulphonating agent, for the sulfonation of most of aromatics; Sulphur trioxide is fiercer sulphonating agent, owing to producing by product, is generally be dissolved in solvent using.In addition, the temperature controlling sulfonation reaction is extremely important, and when temperature is low, sulfonic group easily enters substituent ortho position, and during temperature height, sulfonic group easily enters substituent contraposition.When using catalyzer in sulfonation reaction, the direction of malleable sulfonation reaction, this is also a feature of sulfonation reaction.The catalyzer of sulfonation reaction is usually the vitriol of sodium Metal 99.5, mercury, cadmium, aluminium, lead, arsenic, bismuth and iron and the mixture of Vanadium Pentoxide in FLAKES; Silicon oxide and bone black are also a kind of sulfonation catalysts preferably.But utilize the sulfonation reaction of methyl catechol to prepare highly purified thiocol, namely the 4-hydroxy 3-methoxybenzene potassium sulfonate of single structure has larger difficulty, is necessary the synthetic route that research and development one are new.Further, there is not been reported to prepare the patent of invention technology of the 4-hydroxy 3-methoxybenzene potassium sulfonate target product of single structure.
Summary of the invention
Technical problem to be solved by this invention is, provides a kind of new reaction raw material cheap and easy to get, gentle at reaction conditions, aftertreatment simple and be suitable for the synthetic method of high-purity guaiacol potassium sulfonate of large-scale production.
For solving above technical problem, the preparation method of thiocol of the present invention, in turn includes the following steps:
A, with structure such as formula the 2-hydroxyacetanilide shown in (I) for raw material, carry out sulfonation reaction with the sulphur trioxide be dissolved in organic solvent and obtain 2-hydroxyl-5-sulfonic group Acetanilide, and concentrated;
B, carry out kharophen hydrolysis and diazotization reaction in acid condition, especially by adding dilute hydrochloric acid and slowly drip sodium nitrite solution in reactant, realize 2-hydroxyl-5-sulfonic group Acetanilide and kharophen hydrolysis occurs in acid condition, the nitrous acid generation diazotization reaction simultaneously generated in hydrolysate and solution;
C, gained diazonium salt carry out methoxylation with the methanol solution containing potassium hydroxide and obtain structure such as formula the 3-methoxyl group-4-hydroxy benzenesulfonic acid shown in (II);
D, then separation and purification in Klorvess Liquid, obtained purity reaches the structure of more than 99% such as formula the 4-hydroxy 3-methoxybenzene potassium sulfonate target product shown in (III), Klorvess Liquid makes this target product be easy to precipitate and separate while making 3-methoxyl group-4-hydroxy benzenesulfonic acid be converted into 4-hydroxy 3-methoxybenzene potassium sulfonate:
。
Further, during sulfonation reaction, organic solvent used can be selected from combination that is one of following or more than one solvents: methylene dichloride, chloroform, tetrachloroethane, dioxane, pyridine.
Further, described organic solvent is preferably one in tetrachloroethane, dioxane or its mixture.
Further, described organic solvent most preferably is the mixture of tetrachloroethane and dioxane, and its volume ratio is 1: 1 ~ 10.
Further, the volumetric usage of described organic solvent counts 5 ~ 10 mL/g with the quality of 2-hydroxyacetanilide.
Further, described 2-hydroxyacetanilide and the molar ratio of sulphur trioxide are 1: 1 ~ 3.
Further, described 2-hydroxyacetanilide and the molar ratio of sulphur trioxide are 1: 1 ~ 1.5.
Further, in diazotization reaction, the mole number of nitrous acid is 3 ~ 5 times of 2-hydroxyacetanilide.
Further, sulfonation reaction temperature is 60 ~ 90 DEG C, diazotization reaction temperature is 0 ~ 5 DEG C, methoxylation temperature is 50 ~ 100 DEG C.
Further, the described methoxylation time is 5 ~ 10 hours.
It is reaction raw materials that the present invention have selected this material cheap and easy to get of 2-hydroxyacetanilide, pass through sulfonation reaction, sulfonic group is introduced in hydroxyl contraposition, and make kharophen that hydrolysis and diazotization reaction occur, and the performance utilizing gained diazonium salt directly can introduce methoxyl group in containing the basic solution of methyl alcohol prepares 3-methoxyl group-4-hydroxy benzenesulfonic acid, target product 4-hydroxy 3-methoxybenzene potassium sulfonate is converted into again further in Klorvess Liquid, it is a brand-new reaction scheme preparing thiocol, and products therefrom structure is single, 4-hydroxy 3-methoxybenzene potassium sulfonate purity reaches more than 99%, to sum up, reaction raw materials of the present invention is cheap and easy to get, reaction conditions is gentle, aftertreatment is simple and be suitable for large-scale production.
Embodiment
With specific embodiment, technical scheme of the present invention is described below, but protection scope of the present invention is not limited thereto:
embodiment 1
In 500 milliliters of there-necked flasks, add 2-hydroxyacetanilide 15.1 grams (0.1 mole), dioxane 150 milliliters, sulphur trioxide 9.6 grams (0.12 mole), react under 80 DEG C of conditions, follow the tracks of reaction raw materials with thin-layer chromatography to disappear, add 20%(quality again) dilute hydrochloric acid, dilute hydrochloric acid consumption is as the criterion with wherein containing hydrogen chloride 0.3 mole, slowly drip the aqueous solution 100 milliliters containing Sodium Nitrite 20.7 grams (0.3 mole), control temperature of reaction and be no more than 5 DEG C, the situation of the nitrous acid that dissociates with the inspection of starch-kalium iodide test paper, until reaction terminates.Then obtained diazonium salt solution is slowly added drop-wise in the methanol solution 100 milliliters containing 8 grams of potassium hydroxide, reacts 10 hours at 100 DEG C, add solid potassium chloride 10 grams, stir and make it to dissolve, slowly cool, filter, dry, obtain product 15.7 grams, productive rate 65%, purity >=99%.
embodiment 2
In 500 milliliters of there-necked flasks, add 2-hydroxyacetanilide 15.1 grams (0.1 mole), dioxane and each 75 milliliters of tetrachloroethane, sulphur trioxide 12 grams (0.15 mole), react under 90 DEG C of conditions, follow the tracks of reaction raw materials with thin-layer chromatography to disappear, add 20%(quality again) dilute hydrochloric acid, dilute hydrochloric acid consumption is as the criterion with wherein containing hydrogen chloride 0.5 mole, slowly drip the aqueous solution 100 milliliters containing Sodium Nitrite 35 grams (0.5 mole), control temperature of reaction and be no more than 5 DEG C, the situation of the nitrous acid that dissociates with the inspection of starch-kalium iodide test paper, until reaction terminates.Then obtained diazonium salt solution is slowly added drop-wise in the methanol solution 100 milliliters containing 8 grams of potassium hydroxide, reacts 5 hours at 100 DEG C, add solid potassium chloride 10 grams, stir and make it to dissolve, slowly cool, filter, dry, obtain product 15 grams, productive rate 60%, purity >=99%.
embodiment 3
In 500 milliliters of there-necked flasks, add 2-hydroxyacetanilide 15.1 grams (0.1 mole), tetrachloroethane 150 milliliters, sulphur trioxide 9.6 grams (0.12 mole), react under 60 DEG C of conditions, follow the tracks of reaction raw materials with thin-layer chromatography to disappear, add 20%(quality again) dilute hydrochloric acid, dilute hydrochloric acid consumption is as the criterion with wherein containing hydrogen chloride 0.3 mole, slowly drip the aqueous solution 100 milliliters containing Sodium Nitrite 20.7 grams (0.3 mole), control temperature of reaction and be no more than 5 DEG C, the situation of the nitrous acid that dissociates with the inspection of starch-kalium iodide test paper, until reaction terminates.Then obtained diazonium salt solution is slowly added drop-wise in the methanol solution 100 milliliters containing 8 grams of potassium hydroxide, reacts 5 hours at 100 DEG C, add solid potassium chloride 10 grams, stir and make it to dissolve, slowly cool, filter, dry, obtain product 15.3 grams, productive rate 63%, purity >=99%.
embodiment 4
In 500 milliliters of there-necked flasks, add 2-hydroxyacetanilide 15.1 grams (0.1 mole), dioxane 150 milliliters, sulphur trioxide 8 grams (0.1 mole), react under 90 DEG C of conditions, follow the tracks of reaction raw materials with thin-layer chromatography to disappear, add 20%(quality again) dilute hydrochloric acid, dilute hydrochloric acid consumption is as the criterion with wherein containing hydrogen chloride 0.5 mole, slowly drip the aqueous solution 100 milliliters containing Sodium Nitrite 35 grams (0.5 mole), control temperature of reaction and be no more than 5 DEG C, the situation of the nitrous acid that dissociates with the inspection of starch-kalium iodide test paper, until reaction terminates.Then obtained diazonium salt solution is slowly added drop-wise in the methanol solution 100 milliliters containing 8 grams of potassium hydroxide, reacts 8 hours at 80 DEG C, add solid potassium chloride 10 grams, stir and make it to dissolve, slowly cool, filter, dry, obtain product 15.7 grams, productive rate 65%, purity >=99%.
Above in each embodiment, in dilute hydrochloric acid, the molar ratio of hydrogenchloride and Sodium Nitrite is 1:1, and the mole number of the nitrous acid generated after feeding intake is 3 ~ 5 times of raw material 2-hydroxyacetanilide consumption.
Claims (10)
1. a preparation method for thiocol, is characterized in that the method in turn includes the following steps:
A, with structure such as formula the 2-hydroxyacetanilide shown in (I) for raw material, carry out sulfonation reaction with the sulphur trioxide be dissolved in organic solvent and obtain 2-hydroxyl-5-sulfonic group Acetanilide, and concentrated;
B, carry out kharophen hydrolysis and diazotization reaction in acid condition;
C, gained diazonium salt carry out methoxylation with the methanol solution containing potassium hydroxide and obtain structure such as formula the 3-methoxyl group-4-hydroxy benzenesulfonic acid shown in (II);
D, then separation and purification in Klorvess Liquid, obtained purity reaches the structure of more than 99% such as formula the 4-hydroxy 3-methoxybenzene potassium sulfonate target product shown in (III):
。
2. the preparation method of thiocol according to claim 1, when it is characterized in that sulfonation reaction, organic solvent used can be selected from combination that is one of following or more than one solvents: methylene dichloride, chloroform, tetrachloroethane, dioxane, pyridine.
3. the preparation method of thiocol according to claim 2, is characterized in that described organic solvent is one in tetrachloroethane, dioxane or its mixture.
4. the preparation method of thiocol according to claim 3, it is characterized in that described organic solvent is the mixture of tetrachloroethane and dioxane, its volume ratio is 1: 1 ~ 10.
5. the preparation method of thiocol according to claim 1 and 2, is characterized in that the volumetric usage of described organic solvent counts 5 ~ 10 mL/g with the quality of 2-hydroxyacetanilide.
6. the preparation method of thiocol according to claim 1, is characterized in that the molar ratio of described 2-hydroxyacetanilide and sulphur trioxide is 1: 1 ~ 3.
7. the preparation method of thiocol according to claim 6, is characterized in that the molar ratio of described 2-hydroxyacetanilide and sulphur trioxide is 1: 1 ~ 1.5.
8. the preparation method of thiocol according to claim 1, is characterized in that the mole number of nitrous acid in diazotization reaction is 3 ~ 5 times of 2-hydroxyacetanilide.
9. the preparation method of described thiocol according to claim 1, is characterized in that sulfonation reaction temperature is 60 ~ 90 DEG C, diazotization reaction temperature is 0 ~ 5 DEG C, methoxylation temperature is 50 ~ 100 DEG C.
10. the preparation method of the thiocol according to claim 1 or 9, is characterized in that the described methoxylation time is 5 ~ 10 hours.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105541901A (en) * | 2015-12-21 | 2016-05-04 | 合肥星宇化学有限责任公司 | Preparation method for 2,4-dichloro-5-nitrophenyl phosphotriester |
| CN112824369A (en) * | 2019-11-21 | 2021-05-21 | 万华化学集团股份有限公司 | High-yield vanillin synthesis process |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105541901A (en) * | 2015-12-21 | 2016-05-04 | 合肥星宇化学有限责任公司 | Preparation method for 2,4-dichloro-5-nitrophenyl phosphotriester |
| CN105541901B (en) * | 2015-12-21 | 2018-08-28 | 合肥星宇化学有限责任公司 | A kind of preparation method of bis- chloro- three esters of 5- nitrophenylphosphates of 2,4- |
| CN112824369A (en) * | 2019-11-21 | 2021-05-21 | 万华化学集团股份有限公司 | High-yield vanillin synthesis process |
| CN112824369B (en) * | 2019-11-21 | 2022-11-08 | 万华化学集团股份有限公司 | High-yield vanillin synthesis process |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104311456B (en) | 2016-08-17 |
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Denomination of invention: A preparation method of potassium guaiacol sulfonate Effective date of registration: 20211203 Granted publication date: 20160817 Pledgee: Taizhou Minsheng Bank Co.,Ltd. Pledgor: ZHEJIANG HAIZHOU PHARMACEUTICAL CO.,LTD. Registration number: Y2021330002440 |
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Address after: 317016 coastal industrial zone, Taizhou, Zhejiang, China Patentee after: Zhejiang Haizhou Pharmaceutical Co.,Ltd. Address before: 317016 coastal industrial zone, Taizhou, Zhejiang, China Patentee before: ZHEJIANG HAIZHOU PHARMACEUTICAL CO.,LTD. |