CN104311456B - A kind of preparation method of sulfogaiacol - Google Patents
A kind of preparation method of sulfogaiacol Download PDFInfo
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- 229950006382 sulfogaiacol Drugs 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 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 title claims abstract 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 45
- 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 21
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims abstract description 18
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims abstract description 13
- 239000002994 raw material Substances 0.000 claims abstract description 12
- 239000002253 acid Substances 0.000 claims abstract description 10
- 239000003960 organic solvent Substances 0.000 claims abstract description 10
- FZERHIULMFGESH-UHFFFAOYSA-N N-phenylacetamide Chemical compound CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000006198 methoxylation reaction Methods 0.000 claims abstract description 7
- 239000007788 liquid Substances 0.000 claims abstract description 6
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims abstract description 4
- 229960001413 acetanilide Drugs 0.000 claims abstract description 4
- FHIVAFMUCKRCQO-UHFFFAOYSA-N diazinon Chemical compound CCOP(=S)(OCC)OC1=CC(C)=NC(C(C)C)=N1 FHIVAFMUCKRCQO-UHFFFAOYSA-N 0.000 claims abstract description 4
- 230000007062 hydrolysis Effects 0.000 claims abstract description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 4
- -1 methoxyl group Chemical group 0.000 claims abstract description 4
- 239000012141 concentrate Substances 0.000 claims abstract description 3
- ADVGKWPZRIDURE-UHFFFAOYSA-N 2'-Hydroxyacetanilide Chemical compound CC(=O)NC1=CC=CC=C1O ADVGKWPZRIDURE-UHFFFAOYSA-N 0.000 claims description 28
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 12
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 claims description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 2
- GQPLMRYTRLFLPF-UHFFFAOYSA-N nitrous oxide Inorganic materials [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 claims description 2
- BTCCDEGEFOXTBE-UHFFFAOYSA-N 1-(2-aminophenyl)-2-hydroxyethanone Chemical compound NC1=CC=CC=C1C(=O)CO BTCCDEGEFOXTBE-UHFFFAOYSA-N 0.000 claims 2
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 claims 1
- 229960003750 ethyl chloride Drugs 0.000 claims 1
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- 238000012805 post-processing Methods 0.000 abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 2
- PJFNNMFXEVADGK-UHFFFAOYSA-N 2-hydroxy-n-phenylacetamide Chemical class OCC(=O)NC1=CC=CC=C1 PJFNNMFXEVADGK-UHFFFAOYSA-N 0.000 abstract 1
- IULJSGIJJZZUMF-UHFFFAOYSA-N 2-hydroxybenzenesulfonic acid Chemical class OC1=CC=CC=C1S(O)(=O)=O IULJSGIJJZZUMF-UHFFFAOYSA-N 0.000 abstract 1
- MIBMNQZAMATABQ-UHFFFAOYSA-N [K].C1(=C(O)C(=CC=C1)S(=O)(=O)O)OC Chemical compound [K].C1(=C(O)C(=CC=C1)S(=O)(=O)O)OC MIBMNQZAMATABQ-UHFFFAOYSA-N 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- WTLYFCZMLRAPLI-UHFFFAOYSA-N 2-methoxyphenol;potassium Chemical compound [K].COC1=CC=CC=C1O WTLYFCZMLRAPLI-UHFFFAOYSA-N 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 10
- QFRKWSPTCBGLSU-UHFFFAOYSA-M potassium 4-hydroxy-3-methoxybenzene-1-sulfonate Chemical compound [K+].COC1=CC(S([O-])(=O)=O)=CC=C1O QFRKWSPTCBGLSU-UHFFFAOYSA-M 0.000 description 8
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- 235000010288 sodium nitrite Nutrition 0.000 description 5
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000012954 diazonium Substances 0.000 description 4
- 150000001989 diazonium salts Chemical class 0.000 description 4
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 4
- 239000001103 potassium chloride Substances 0.000 description 4
- 235000011164 potassium chloride Nutrition 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000006277 sulfonation reaction Methods 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- YWBULDWOEPVCNS-UHFFFAOYSA-N [S].COC1=C(C=CC=C1)O Chemical compound [S].COC1=C(C=CC=C1)O YWBULDWOEPVCNS-UHFFFAOYSA-N 0.000 description 3
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 3
- 238000007689 inspection Methods 0.000 description 3
- VIKNJXKGJWUCNN-XGXHKTLJSA-N norethisterone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 VIKNJXKGJWUCNN-XGXHKTLJSA-N 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 206010036790 Productive cough Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 239000003054 catalyst Substances 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
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- LHGVFZTZFXWLCP-UHFFFAOYSA-N guaiacol Chemical compound COC1=CC=CC=C1O LHGVFZTZFXWLCP-UHFFFAOYSA-N 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000001117 sulphuric acid Substances 0.000 description 2
- 235000011149 sulphuric acid Nutrition 0.000 description 2
- 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 1
- OMNGOGILVBLKAS-UHFFFAOYSA-N 2-methoxyphenol Chemical compound COC1=CC=CC=C1O.COC1=CC=CC=C1O OMNGOGILVBLKAS-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical group CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000012670 alkaline solution 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
- 150000001491 aromatic compounds Chemical class 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
- 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
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 239000003172 expectorant agent Substances 0.000 description 1
- 230000003419 expectorant effect Effects 0.000 description 1
- 230000000762 glandular Effects 0.000 description 1
- 229960001867 guaiacol Drugs 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000000147 hypnotic effect Effects 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
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 150000003112 potassium compounds Chemical class 0.000 description 1
- CASUWPDYGGAUQV-UHFFFAOYSA-M potassium;methanol;hydroxide Chemical compound [OH-].[K+].OC CASUWPDYGGAUQV-UHFFFAOYSA-M 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 229910052814 silicon oxide Inorganic materials 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention discloses the preparation method of a kind of sulfogaiacol, in turn include the following steps: A, with the structure 2 hydroxyacetanilides as shown in formula (I) as raw material, carry out sulfonating reaction with the sulfur trioxide being dissolved in organic solvent and prepare 2 hydroxyl 5 sulfonic group acetanilide, and concentrate；B, carry out acetylamino hydrolysis and diazo-reaction in acid condition；C, gained diazol carry out methoxylation with the methanol solution containing potassium hydroxide and obtain the structure 3 methoxyl group 4 hydroxy benzenesulfonic acids as shown in formula (II)；D, then isolated and purified in Klorvess Liquid, prepared purity reaches the structure of more than 99% 4 hydroxyl 3 methoxy benzenesulfonic acid potassium target products as shown in formula (III).Reaction raw materials of the present invention is cheap and easy to get, and reaction condition is gentle, products therefrom structure is single, and post processing is simple and is suitable for large-scale production.
Description
Technical field
The present invention relates to the new synthetic method of a kind of sulfogaiacol, the most highly purified para-position guaiacol sulphur
The synthetic method of acid potassium, belongs to pharmaceutical chemistry technical field.
Background technology
Sulfogaiacol is strength expectorant, makes respiratory tract glandular secretion increase, and sputum is diluted, it is easy to expectoration；
The most atropinic effect of anticholinergic agent can be strengthened；With calmness, hypnotic, antiallergic agent with increasing this product suppression to maincenter
Effect.At present the sulfogaiacol finished product of commercial type may often be such that 4-hydroxy 3-methoxybenzene potassium sulfonate and 3-hydroxyl-
(English name is potassium 4-hydroxy-3-methoxybenzene-sulphonate/ to 4-methoxy benzenesulfonic acid potassium
Potassium 3-hydroxy-4-methoxybenzenesulphonate) mixture.2014, China's guaiacol sulphur
Acid potassium compound medicine sales volume reaches 5MG, within relatively 2013, increases by 25%.30% was increased every year in the past 5 years (2009-2014).City
Field potential of demand is the biggest.
The method of synthesizing guaiacol potassium sulfonate is mainly by guaiacol (o-methoxyphenol) and derivant thereof at present
Carry out sulfonation to prepare.Products therefrom is mainly 4-hydroxy 3-methoxybenzene potassium sulfonate and 3-hydroxyl-4-methoxy benzenesulfonic acid potassium
Mixture, the ratio of substantially 4-hydroxy 3-methoxybenzene potassium sulfonate and 3-hydroxyl-4-methoxy benzenesulfonic acid potassium is 70%: 30%.
The product that only Japan produces can reach 4-hydroxy 3-methoxybenzene potassium sulfonate more than 98%.Due to sulfogaiacol
The drug effect of the mixture of two kinds of isomers is relatively poor, therefore, and developmental research highly purified 4-hydroxy 3-methoxybenzene potassium sulfonate
Product has wide market prospect.
Sulfonating reaction is traditional conventional organic chemical reactions, is that sulfonating agent is directly carried out with sulfonic group replacement hydrogen atom
Reaction.Conventional sulfonating agent has concentrated sulphuric acid, is dissolved in the different solvents such as chlorohydrocarbon, sulfur dioxide liquid, dioxane and pyridine
In the mixture of sulfur trioxide, chlorosulfonic acid, sulfur dioxide and chlorine and chlorosulfuric acid etc..Sulphuric acid is a kind of relatively mild sulfonation
Agent, for the sulfonation of most of aromatic compounds；Sulfur trioxide is fiercer sulfonating agent, owing to by-product can be produced, and one
As be dissolved in solvent use.It addition, the temperature controlling sulfonating reaction is extremely important, when temperature is low, sulfonic group easily enters replacement
The ortho position of base, during temperature height, sulfonic group easily enters the para-position of substituent group.When using catalyst in sulfonating reaction, malleable
The direction of sulfonating reaction, this is also a feature of sulfonating reaction.The catalyst of sulfonating reaction may often be such that metallic sodium, hydrargyrum, cadmium,
The sulfate of aluminum, lead, arsenic, bismuth and ferrum and the mixture of vanadic anhydride；Silicon oxide and bone black are also that a kind of preferably sulfonation is urged
Agent.But the sulfonating reaction utilizing guaiacol prepare the 4-hydroxyl of highly purified sulfogaiacol, i.e. single structure-
3-methoxy benzenesulfonic acid potassium has bigger difficulty, it is necessary to research and develop a new synthetic route.Further, single structure is prepared
The patent of invention technology of 4-hydroxy 3-methoxybenzene potassium sulfonate target product there is not been reported.
Summary of the invention
The technical problem to be solved is to provide a kind of new reaction raw material cheap and easy to get, in reaction condition temperature
Simple with, post processing 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 sulfogaiacol of the present invention, include as follows successively
Step:
A, with structure 2-hydroxyacetanilide as shown in formula (I) as raw material, with the sulfur trioxide being dissolved in organic solvent
Carry out sulfonating reaction and prepare 2-hydroxyl-5-sulfonic group acetanilide, and concentrate；
B, carry out acetylamino hydrolysis and diazo-reaction in acid condition, especially by adding dilute salt in reactant
Acid and be slowly added dropwise sodium nitrite solution, it is achieved there is acetyl ammonia in acid condition in 2-hydroxyl-5-sulfonic group acetanilide
Base hydrolyzes, simultaneously hydrolyzate and the nitrous acid generation diazo-reaction of generation in solution；
C, gained diazol carry out methoxylation with the methanol solution containing potassium hydroxide and obtain structure such as formula (II)
Shown 3-methoxyl group-4-hydroxy benzenesulfonic acid；
D, then isolated and purified in Klorvess Liquid, prepared purity reaches the structure of more than 99% as shown in formula (III)
4-hydroxy 3-methoxybenzene potassium sulfonate target product, Klorvess Liquid makes 3-methoxyl group-4-hydroxy benzenesulfonic acid be converted into 4-hydroxyl
While base-3-methoxy benzenesulfonic acid potassium, this target product is made to be prone to precipitate and separate:
。
Further, during sulfonating reaction, organic solvent used is selected from one of the following or combination of more than one solvents: two
Chloromethanes, chloroform, sym-tetrachloroethane, dioxane, pyridine.
Further, the one during described organic solvent is preferably sym-tetrachloroethane, dioxane or its mixture.
Further, described organic solvent is most preferably the mixture of sym-tetrachloroethane and dioxane, and its volume ratio is 1:
1～10.
Further, the volumetric usage of described organic solvent is calculated as 5～10 mL/g with the quality of 2-hydroxyacetanilide.
Further, described 2-hydroxyacetanilide is 1: 1～3 with the molar ratio of sulfur trioxide.
Further, described 2-hydroxyacetanilide is 1: 1～1.5 with the molar ratio of sulfur trioxide.
Further, in diazo-reaction, the molal quantity of nitrous acid is 3～5 times of 2-hydroxyacetanilide.
Further, sulfonating reaction temperature be 60～90 DEG C, diazo-reaction temperature be 0～5 DEG C, methoxylation temperature
Degree 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, by sulfonating reaction,
Hydroxyl para-position introduces sulfonic group, and makes acetylamino that hydrolysis and diazo-reaction to occur, and utilize gained diazol to exist
The performance that can be introduced directly into methoxyl group in alkaline solution containing methanol prepares 3-methoxyl group-4-hydroxy benzenesulfonic acid, then enters
One step is converted into target product 4-hydroxy 3-methoxybenzene potassium sulfonate in Klorvess Liquid, is one and prepares guaiacol sulphur
The brand-new reaction scheme of acid potassium, 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, and reaction condition is gentle, post processing is simple and is suitable for large-scale production.
Detailed description of the invention
With specific embodiment, technical scheme is described below, but protection scope of the present invention is not limited to this:
Embodiment 1
In 500 milliliters of there-necked flasks, add 2-hydroxyacetanilide 15.1 grams (0.1 mole), dioxane 150 milli
Rise, sulfur trioxide 9.6 grams (0.12 mole), react under the conditions of 80 DEG C, follow the tracks of reaction raw materials with thin layer chromatography and disappear, add
20%(mass) dilute hydrochloric acid, dilute hydrochloric acid consumption is as the criterion with wherein containing hydrogen chloride 0.3 mole, and slowly dropping is containing sodium nitrite 20.7
The aqueous solution 100 milliliters of gram (0.3 mole), controls reaction temperature less than 5 DEG C, with the free Asia of starch-kalium iodide reagent paper inspection
The situation of nitric acid, until reaction terminates.Then prepared diazonium salt solution is slowly dropped to the methanol containing 8 grams of potassium hydroxide
In solution 100 milliliters, reacting 10 hours at 100 DEG C, add solid potassium chloride 10 grams, stirring is allowed to dissolve, and slowly cools down, mistake
Filter, is dried, obtains product 15.7 grams, productivity 65%, purity >=99%.
Embodiment 2
In 500 milliliters of there-necked flasks, add 2-hydroxyacetanilide 15.1 grams (0.1 mole), dioxane and tetrachloro
Each 75 milliliters of ethane, sulfur trioxide 12 grams (0.15 mole), reacts under the conditions of 90 DEG C, follows the tracks of reaction raw materials with thin layer chromatography and disappear
Lose, add 20%(mass) dilute hydrochloric acid, dilute hydrochloric acid consumption is as the criterion with wherein containing hydrogen chloride 0.5 mole, and slowly dropping is containing nitrous
The aqueous solution 100 milliliters of 35 grams of sodium of acid (0.5 mole), controls reaction temperature and is less than 5 DEG C, check with starch-kalium iodide reagent paper
The situation of free nitrous acid, until reaction terminates.Then prepared diazonium salt solution is slowly dropped to containing 8 grams of potassium hydroxide
Methanol solution 100 milliliters in, at 100 DEG C react 5 hours, add solid potassium chloride 10 grams, stirring be allowed to dissolve, the coldest
But, filter, be dried, obtain product 15 grams, productivity 60%, purity >=99%.
Embodiment 3
In 500 milliliters of there-necked flasks, add 2-hydroxyacetanilide 15.1 grams (0.1 mole), sym-tetrachloroethane 150 milli
Rise, sulfur trioxide 9.6 grams (0.12 mole), react under the conditions of 60 DEG C, follow the tracks of reaction raw materials with thin layer chromatography and disappear, add
20%(mass) dilute hydrochloric acid, dilute hydrochloric acid consumption is as the criterion with wherein containing hydrogen chloride 0.3 mole, and slowly dropping is containing sodium nitrite 20.7
The aqueous solution 100 milliliters of gram (0.3 mole), controls reaction temperature less than 5 DEG C, with the free Asia of starch-kalium iodide reagent paper inspection
The situation of nitric acid, until reaction terminates.Then prepared diazonium salt solution is slowly dropped to the methanol containing 8 grams of potassium hydroxide
In solution 100 milliliters, reacting 5 hours at 100 DEG C, add solid potassium chloride 10 grams, stirring is allowed to dissolve, and slowly cools down, mistake
Filter, is dried, obtains product 15.3 grams, productivity 63%, purity >=99%.
Embodiment 4
In 500 milliliters of there-necked flasks, add 2-hydroxyacetanilide 15.1 grams (0.1 mole), dioxane 150 milli
Rise, sulfur trioxide 8 grams (0.1 mole), react under the conditions of 90 DEG C, follow the tracks of reaction raw materials with thin layer chromatography and disappear, add 20%
(quality) dilute hydrochloric acid, dilute hydrochloric acid consumption is as the criterion with wherein containing hydrogen chloride 0.5 mole, and slowly dropping contains sodium nitrite 35 gram (0.5
Mole) aqueous solution 100 milliliters, control reaction temperature less than 5 DEG C, dissociate nitrous acid with starch-kalium iodide reagent paper inspection
Situation, until reaction terminates.Then prepared diazonium salt solution is slowly dropped to the methanol solution containing 8 grams of potassium hydroxide
In 100 milliliters, reacting 8 hours at 80 DEG C, add solid potassium chloride 10 grams, stirring is allowed to dissolve, and slowly cools down, and filters, dry
Dry, obtain product 15.7 grams, productivity 65%, purity >=99%.
In various embodiments above, in dilute hydrochloric acid, hydrogen chloride is 1:1 with the molar ratio of sodium nitrite, generates after feeding intake
The molal quantity of nitrous acid is 3～5 times of raw material 2-hydroxyacetanilide consumption.
Claims (8)
1. the preparation method of a sulfogaiacol, it is characterised in that the method in turn includes the following steps:
A, with structure 2-hydroxyacetanilide as shown in formula (I) as raw material, carry out with the sulfur trioxide being dissolved in organic solvent
Sulfonating reaction prepares 2-hydroxyl-5-sulfonic group acetanilide, and concentrates；
B, carry out acetylamino hydrolysis and diazo-reaction in acid condition；
C, gained diazol and the methanol solution containing potassium hydroxide carry out methoxylation and obtain shown in structure such as formula (II)
3-methoxyl group-4-hydroxy benzenesulfonic acid；
D, then isolated and purified in Klorvess Liquid, prepared purity reaches the structure of more than 99% 4-as shown in formula (III)
Hydroxy 3-methoxybenzene potassium sulfonate target product:
Described organic solvent is the one in sym-tetrachloroethane, dioxane or its mixture.
The preparation method of sulfogaiacol the most according to claim 1, it is characterised in that described organic solvent is four
Ethyl chloride and the mixture of dioxane, its volume ratio is 1:1～10.
The preparation method of sulfogaiacol the most according to claim 1 and 2, it is characterised in that described organic solvent
Volumetric usage is calculated as 5～10mL/g with the quality of 2-hydroxyacetanilide.
The preparation method of sulfogaiacol the most according to claim 1, it is characterised in that described 2-glycoloyl
Aniline is 1:1～3 with the molar ratio of sulfur trioxide.
The preparation method of sulfogaiacol the most according to claim 4, it is characterised in that described 2-glycoloyl
Aniline is 1:1～1.5 with the molar ratio of sulfur trioxide.
The preparation method of sulfogaiacol the most according to claim 1, it is characterised in that nitrous in diazo-reaction
Molal quantity is 2-hydroxyacetanilide 3～5 times of acid.
The preparation method of described sulfogaiacol the most according to claim 1, it is characterised in that sulfonating reaction temperature
Degree is 60～90 DEG C, diazo-reaction temperature is 0～5 DEG C, methoxylation temperature is 50～100 DEG C.
8. according to the preparation method of the sulfogaiacol described in claim 1 or 7, it is characterised in that described methoxylation is anti-
It is 5～10 hours between Ying Shi.
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| GB190516723A (en) * | 1905-08-17 | 1906-02-15 | Reginald Eaton Ellis | New or Improved Manufacture of Guaiacol Sulphonic Acids and Salts thereof. |
| GB190912745A (en) * | 1909-05-29 | 1909-12-16 | Jasper Wetter | Process for the Manufacture of Guaiacol-sulphonic Acid and its Salts. |
| CN1569788A (en) * | 2003-07-11 | 2005-01-26 | 上海欣晨新技术公司 | Process for continuous hydrolysis synthesis of guaiacol |
| CN104086383A (en) * | 2014-06-16 | 2014-10-08 | 安徽佑骏商品混凝土有限公司 | Guaiacol preparation method |
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2014
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB190516723A (en) * | 1905-08-17 | 1906-02-15 | Reginald Eaton Ellis | New or Improved Manufacture of Guaiacol Sulphonic Acids and Salts thereof. |
| GB190912745A (en) * | 1909-05-29 | 1909-12-16 | Jasper Wetter | Process for the Manufacture of Guaiacol-sulphonic Acid and its Salts. |
| CN1569788A (en) * | 2003-07-11 | 2005-01-26 | 上海欣晨新技术公司 | Process for continuous hydrolysis synthesis of guaiacol |
| CN104086383A (en) * | 2014-06-16 | 2014-10-08 | 安徽佑骏商品混凝土有限公司 | Guaiacol preparation method |
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| Cerfontain Hans等.Aromatic sulfonation. Part 107. Reactions of the dihydroxybenzenes and heir methyl ethers with sulfur trioxide. The effect of initial sulfation on the sulfonation product distribution.《Recueil des Travaux Chimiques des Pays-Bas》.1989,第108卷(第1期),7-13页. * |
| 李光明等.重氮盐水解制备愈创木酚的实验工艺研究.《化工中间体》.2010,(第3期),57-62页. * |
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