CN116606231A - P-sulfonamide phenylhydrazine hydrochloride and preparation method thereof - Google Patents
P-sulfonamide phenylhydrazine hydrochloride and preparation method thereof Download PDFInfo
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- CN116606231A CN116606231A CN202310579095.6A CN202310579095A CN116606231A CN 116606231 A CN116606231 A CN 116606231A CN 202310579095 A CN202310579095 A CN 202310579095A CN 116606231 A CN116606231 A CN 116606231A
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- 229940124530 sulfonamide Drugs 0.000 title claims abstract description 114
- 229940038531 phenylhydrazine hydrochloride Drugs 0.000 title claims abstract description 72
- 238000002360 preparation method Methods 0.000 title claims abstract description 39
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 108
- 238000006243 chemical reaction Methods 0.000 claims abstract description 61
- 238000006722 reduction reaction Methods 0.000 claims abstract description 40
- 238000006193 diazotization reaction Methods 0.000 claims abstract description 39
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 claims abstract description 36
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 claims abstract description 25
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 19
- 239000012954 diazonium Substances 0.000 claims abstract description 16
- 150000001989 diazonium salts Chemical class 0.000 claims abstract description 16
- 230000009467 reduction Effects 0.000 claims abstract description 13
- 238000003756 stirring Methods 0.000 claims abstract description 9
- XZMIAZCXISFPEJ-UHFFFAOYSA-N 4-aminobenzenesulfonamide;hydrochloride Chemical compound Cl.NC1=CC=C(S(N)(=O)=O)C=C1 XZMIAZCXISFPEJ-UHFFFAOYSA-N 0.000 claims abstract description 8
- 230000009471 action Effects 0.000 claims abstract description 6
- 238000002156 mixing Methods 0.000 claims abstract description 6
- 239000007788 liquid Substances 0.000 claims abstract description 5
- 239000000243 solution Substances 0.000 claims description 98
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 54
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical group [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 28
- 235000010288 sodium nitrite Nutrition 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 230000008569 process Effects 0.000 claims description 14
- 230000035484 reaction time Effects 0.000 claims description 14
- 235000010265 sodium sulphite Nutrition 0.000 claims description 14
- 238000001816 cooling Methods 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 7
- 235000019441 ethanol Nutrition 0.000 claims description 7
- 239000007787 solid Substances 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 238000010009 beating Methods 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 238000007670 refining Methods 0.000 claims description 5
- 150000003456 sulfonamides Chemical class 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 2
- AZFNGPAYDKGCRB-XCPIVNJJSA-M [(1s,2s)-2-amino-1,2-diphenylethyl]-(4-methylphenyl)sulfonylazanide;chlororuthenium(1+);1-methyl-4-propan-2-ylbenzene Chemical compound [Ru+]Cl.CC(C)C1=CC=C(C)C=C1.C1=CC(C)=CC=C1S(=O)(=O)[N-][C@@H](C=1C=CC=CC=1)[C@@H](N)C1=CC=CC=C1 AZFNGPAYDKGCRB-XCPIVNJJSA-M 0.000 claims description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 235000010289 potassium nitrite Nutrition 0.000 claims description 2
- 239000004304 potassium nitrite Substances 0.000 claims description 2
- 230000001105 regulatory effect Effects 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- FATGUJMZNUEQIV-UHFFFAOYSA-N (4-sulfonylcyclohexa-1,5-dien-1-yl)hydrazine hydrochloride Chemical compound Cl.S(=O)(=O)=C1CC=C(C=C1)NN FATGUJMZNUEQIV-UHFFFAOYSA-N 0.000 claims 3
- 239000012535 impurity Substances 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 239000005416 organic matter Substances 0.000 abstract description 2
- 230000000052 comparative effect Effects 0.000 description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Inorganic materials [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 10
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 8
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 238000004537 pulping Methods 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 229950000244 sulfanilic acid Drugs 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 229960000590 celecoxib Drugs 0.000 description 2
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 238000005265 energy consumption Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000000049 pigment Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- -1 sulfamide phenylhydrazine hydrochloride Chemical compound 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- MGWGWNFMUOTEHG-UHFFFAOYSA-N 4-(3,5-dimethylphenyl)-1,3-thiazol-2-amine Chemical compound CC1=CC(C)=CC(C=2N=C(N)SC=2)=C1 MGWGWNFMUOTEHG-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 1
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 1
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 229940111134 coxibs Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000002845 discoloration Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- JCXJVPUVTGWSNB-UHFFFAOYSA-N nitrogen dioxide Inorganic materials O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 238000010587 phase diagram Methods 0.000 description 1
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 1
- 229940067157 phenylhydrazine Drugs 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- BPSUJSDZHLTNJR-UHFFFAOYSA-N sulfamide;hydrochloride Chemical compound Cl.NS(N)(=O)=O BPSUJSDZHLTNJR-UHFFFAOYSA-N 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
-
- 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
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The application belongs to the technical field of organic matter synthesis, and particularly relates to p-sulfonamide phenylhydrazine hydrochloride and a preparation method thereof. The application provides a preparation method of p-sulfonamide phenylhydrazine hydrochloride, which comprises the following steps: mixing a nitrite solution and a sulfanilamide hydrochloride solution, and sequentially carrying out diazotization reaction, reduction reaction, hydrolysis reaction and salification reaction to obtain p-sulfonamide phenylhydrazine hydrochloride; in the diazotization reaction step, the reaction temperature is 40-60 ℃; in the diazotization reaction step, the sulfanilamide hydrochloric acid solution and nitrite enter the bottom of a reaction kettle, and under the stirring action, the feed liquid turns upwards from the bottom to reach a discharge hole, so that the generated diazonium salt enters a reduction tank. The application adopts medium temperature diazotization, has mild reaction conditions, easy operation, good product quality and less impurities.
Description
Technical Field
The application belongs to the technical field of organic matter synthesis, and particularly relates to p-sulfonamide phenylhydrazine hydrochloride and a preparation method thereof.
Background
P-sulfonamide phenylhydrazine hydrochloride is an important intermediate for synthesizing a nonsteroidal anti-inflammatory drug celecoxib, celecoxib is a novel selective COX-2 inhibitor, and the effects of resisting inflammation, easing pain and bringing down fever are achieved by selectively inhibiting COX-2 to prevent the synthesis of prostaglandin medicaments, so that the p-sulfonamide phenylhydrazine hydrochloride is widely used for treating diseases such as rheumatoid arthritis, rheumatic arthritis and the like.
In the conventional preparation process of p-sulfonamide phenylhydrazine hydrochloride, kettle-type reaction is generally adopted, sodium nitrite solution is dripped into sulfanilamide hydrochloric acid solution for diazotization, the temperature is relatively low, the temperature is generally controlled at-5 ℃, the energy consumption is too high, the reaction time is long, the generated diazonium salt cannot be removed in time in a reaction kettle, and the diazonium salt is easy to react with raw materials in a coupling way, so that byproducts are increased; although the tubular reaction has short residence time and few coupling byproducts, the pipeline reactor is unsatisfactory in terms of productivity.
Disclosure of Invention
Aiming at the defects in the prior art, the application provides the p-sulfonamide phenylhydrazine hydrochloride and the preparation method thereof, which are mild in preparation method, short in reaction time, high in productivity (the yield of p-sulfonamide phenylhydrazine hydrochloride produced in unit time), stable in process (the yield and the purity are stable), and few in impurities and high in purity of the subsequently produced p-sulfonamide phenylhydrazine hydrochloride.
In view of the above technical drawbacks, one of the objects of the present application is to provide a method for preparing p-sulfonamide phenylhydrazine hydrochloride. The second purpose of the application is to provide the p-sulfonamide phenylhydrazine hydrochloride prepared by the preparation method.
In a first aspect, the application provides a method for preparing p-sulfonamide phenylhydrazine hydrochloride, comprising the following steps:
mixing a nitrite solution and a sulfanilamide hydrochloride solution, and sequentially carrying out diazotization reaction, reduction reaction, hydrolysis reaction and salification reaction to obtain p-sulfonamide phenylhydrazine hydrochloride;
in the diazotization reaction step, the reaction temperature is 40-60 ℃;
in the diazotization reaction step, the sulfanilamide hydrochloric acid solution and nitrite enter the bottom of a reaction kettle, and under the stirring action, the feed liquid turns upwards from the bottom to reach a discharge hole, so that the generated diazonium salt enters a reduction tank.
In the application, the diazotization reaction temperature is too high, so that diazonium salt is easy to decompose, and the yield and quality of the sulfamide phenylhydrazine hydrochloride are influenced. The diazotization reaction has the advantages of excessively low temperature, long time and low yield. In the diazotization reaction process, sulfanilamide and nitrite enter the bottom of the reaction kettle, under the action of stirring, the feed liquid turns upwards from the bottom to reach a discharge port, so that diazonium salt enters a reduction tank, the whole diazotization reaction process is complete in material reaction, the time is short, and the diazonium salt can be timely removed from a reaction system, thereby avoiding the use of low temperature.
In the above preparation method, as a preferred embodiment, the sulfanilamide hydrochloride solution and the nitrite simultaneously enter the bottom of the reaction kettle or the sulfanilamide hydrochloride solution enters the bottom of the reaction kettle for 2-5 seconds later than the sodium nitrite enters the bottom of the reaction kettle.
In the application, the molar ratio of the sodium nitrite to the sulfanilic acid is adjusted by controlling the flow rate ratio of the nitrite solution to the sulfanilic acid solution. However, the flow rate is too small, so that the residence time of the materials in the reaction kettle is prolonged, the back mixing phenomenon occurs, the byproducts are increased, the reaction is incomplete, and the yield of the product is reduced. When the nitrite is excessive, the nitrite solution flowmeter is started first, and then the sulfonamide hydrochloride solution flowmeter is started after 3 seconds, because the nitrite is excessive in the diazotization reaction process, so that the just-entered sulfonamide is completely reacted, the nitrite needs to be firstly entered into a reaction system, and if the nitrite is simultaneously started, the sulfonamide can not completely react just at the beginning, and the sulfonamide remains. The control of temperature by starting saline water is the normal operation of a factory, the diazotization reaction kettle is jacketed, materials react in the reaction kettle, and the temperature of the reaction is controlled to be 40-60 ℃ by using the saline water in the jacket, because the diazotization reaction is exothermic, if the temperature of the saline water is not reduced, the reaction is overtemperature, and the decomposition of diazonium salt is caused.
In the above preparation method, as a preferred embodiment, in the diazotizing step, the reaction time is 3 to 5min;
and/or in the step of reduction reaction, the temperature of the reduction reaction is 80-100 ℃, and the pH environment of the reduction reaction is 6-7.
In the present application, the low temperature of the reduction reaction results in slow reduction reaction, which results in lower yield of p-sulfonamide phenylhydrazine hydrochloride, and the reduction reaction is required to be carried out in an acidic environment (pH 6-7), but the pH is not too low, if too low, sulfite becomes sulfur dioxide gas, which further affects the amount of reducing agent used.
In the above preparation method, as a preferred embodiment, in the hydrolysis reaction step, a hydrochloric acid solution is added to perform a reaction, and the mass ratio of the hydrochloric acid solution to the sulfanilamide is (2-4): 1, a step of;
in the salification reaction step, hydrochloric acid solution is added for stirring reaction, and the mass ratio of the hydrochloric acid solution to the sulfanilamide is (1.5-3.5): 1, a step of;
in the present application, the hydrolysis reaction is performed in an acidic environment by adding hydrochloric acid, but if the addition amount of the hydrochloric acid solution is too large, waste is caused, and if the addition amount of the hydrochloric acid solution is too low, sodium sulfite cannot be further neutralized, resulting in incomplete hydrolysis. In the salification reaction, the hydrochloric acid solution is added at the end of the reaction, so that the 4-sulfonamide phenylhydrazine is salified to fully precipitate crystals, and when the addition amount of the hydrochloric acid is too large or too small, the finished product of the p-sulfonamide phenylhydrazine hydrochloride cannot be precipitated from the water phase, the yield is low, the addition amount of the hydrochloric acid is large, the precipitated p-sulfonamide phenylhydrazine hydrochloride has good water solubility and can be dissolved in water, so that the yield of the p-sulfonamide phenylhydrazine hydrochloride is reduced.
In the above preparation method, as a preferred embodiment, in the diazotizing step, the flow rate of the sodium nitrite solution into the diazotizing reaction tank is 0.5 to 1.0m 3 /h；
And/or the flow rate of the sulfanilamide hydrochloric acid solution entering the diazotization reaction tank is 1-2m 3 /h；
And/or the pH value of the diazonium salt solution obtained after the diazotization reaction is finished is between 1.0 and 1.5.
In the application, the diazotization reaction comprises the following specific steps: firstly, turning on a nitrite solution flowmeter, then turning on a sulfahydrochloric acid solution flowmeter after 3 seconds, turning on saline water to control the temperature, and adjusting the flow rates of the nitrite solution and the sulfahydrochloric acid solution to be 0.5-1.0m respectively 3 /h and 1.0-2.0m 3 /h；
The final point of the diazonium salt solution is measured by using a starch-potassium iodide solution at the outlet, the color of the diazonium salt solution is changed into blue, the acidity is measured by using a pH test paper with the pH value of 0.5-5.0, and the pH value is 1.0-1.5.
In the application, pH and starch potassium iodide test paper are used for verifying whether diazotization is completed or not, after the sulfanilamide reaction is completed, excessive sodium nitrite can react with potassium iodide to generate iodine elementary substance, so that starch turns blue, and if the starch turns blue, the situation that the sodium nitrite amount is insufficient and sulfanilamide possibly does not completely react is indicated. The pH is controlled to ensure that the acidity is not too strong in the diazotization reaction process, and if the acidity is too strong, sodium nitrite can be changed into nitrous acid to be decomposed into nitric oxide and nitrogen dioxide, so that the waste of the sodium nitrite is caused.
In the above preparation method, as a preferred embodiment, the mass content of nitrite in the nitrite solution is 18-21%;
and/or, in the sulfanilamide hydrochloric acid solution, the mass content of sulfanilamide is 15-23%, and the mass content of HCl is 10.8-16.6%;
and/or the mass fraction of the hydrochloric acid is 35-36.5%;
and/or the nitrite comprises one of sodium nitrite and potassium nitrite, preferably sodium nitrite.
In the application, the sulfanilamide hydrochloric acid solution is prepared by mixing and stirring sulfanilamide, hydrochloric acid and water.
In the above production method, as a preferred embodiment, in the reduction reaction step, the time of the reduction reaction is 1 to 2 hours.
During the reduction reaction, adding a reducing agent;
and/or the reducing agent is sodium sulfite solution;
and/or the mass fraction of the sodium sulfite aqueous solution is 25-33%;
and/or, the molar ratio of the sulfanilamide to the sodium sulfite in the sodium sulfite solution is 1: (2.6-4).
In the above preparation method, in the reduction reaction step, the manner of adjusting the pH includes adding sodium hydroxide, sodium carbonate, ammonia water or introducing ammonia gas.
In the present application, if the pH is less than 6, sulfite is converted into sulfur dioxide gas, and the reduction is not performed, and if the pH is more than 7, the reducing agent is not performed because a weak acid environment is required for the reduction reaction.
In the above preparation method, as a preferred embodiment, in the hydrolysis reaction step, the hydrochloric acid solution is added at a rate of 0.8 to 1.2m 3 /h；
And/or the mass fraction of the hydrochloric acid solution is 35-36.5%.
In the application, the hydrochloric acid solution is added at a rate that does not flush with SO 2 Can be absorbed as a result of the addition of hydrochloric acid to react sulfite with hydrogen ions to produce sulfur dioxide when the hydrolysis reaction is carried out after the reduction reaction has ended.
In the above preparation method, as a preferred embodiment, the temperature of the hydrolysis reaction is 80 to 100 ℃;
and/or the hydrolysis reaction time is 3-5h.
In the above preparation method, as a preferred embodiment, the temperature of the salification reaction is 80-100 ℃;
and/or the salification reaction time is 10-20min;
and/or the mass fraction of the hydrochloric acid solution added in the salification reaction is 35-36.5%.
In the above preparation method, as a preferred embodiment, cooling is performed after the salification reaction is completed;
and/or the average cooling rate is 0.1-1 ℃/min;
and/or the temperature after the temperature reduction is 15-25 ℃.
In the above preparation method, as a preferred embodiment, the method further comprises steps of refining, centrifuging and drying after the salification reaction.
In the above preparation method, as a preferred embodiment, in the refining step, the solid p-sulfonamide phenylhydrazine hydrochloride is beaten.
In the refining step, the beating temperature is 60-80 ℃ and the time is 10-20min;
and/or the beating adopts an alcohol solvent, wherein the alcohol solvent comprises one of absolute ethyl alcohol, methanol and isopropanol;
and/or, the mass ratio of the sulfanilamide to the absolute ethyl alcohol is 1: (5-8);
and/or the drying temperature is 50-60 ℃.
In the application, the solid p-sulfonamide phenylhydrazine hydrochloride is added into ethanol for pulping, and the characteristics that the p-sulfonamide phenylhydrazine hydrochloride is insoluble in an alcohol solvent and the organic impurities are soluble in the alcohol solvent are utilized, so that the purity of the p-sulfonamide phenylhydrazine hydrochloride is improved by washing away the organic impurities and pigments under the condition of not affecting the yield. If the water phase is dissolved at high temperature and the impurities are removed by cooling crystallization, the yield is reduced.
In a second aspect, the present application provides a p-sulfonamide phenylhydrazine hydrochloride prepared by the method for preparing p-sulfonamide phenylhydrazine hydrochloride provided in the first aspect.
Compared with the prior art, the application has at least one of the following beneficial effects:
1. the application provides a preparation method of p-sulfonamide phenylhydrazine hydrochloride, which comprises the following steps: mixing a nitrite solution and a sulfanilamide hydrochloride solution, and sequentially carrying out diazotization reaction, reduction reaction, hydrolysis reaction and salification reaction to obtain p-sulfonamide phenylhydrazine hydrochloride; in the diazotization reaction step, the reaction temperature is 40-60 ℃; in the diazotization reaction step, the sulfanilamide hydrochloric acid solution and nitrite enter the bottom of a reaction kettle, and under the stirring action, the feed liquid turns upwards from the bottom to reach a discharge hole, so that the generated diazonium salt enters a reduction tank. According to the application, sulfanilamide is used as a raw material, sodium nitrite is added under the action of hydrochloric acid to carry out diazotization reaction, and sodium sulfite is used for thermal reduction; then adding hydrochloric acid for hydrolysis, adding hydrochloric acid for salifying after the hydrolysis, finally cooling for crystallization, and centrifuging to obtain the finished product p-sulfonamide phenylhydrazine hydrochloride. The application adopts medium temperature diazotization, has mild reaction conditions, easy operation, good product quality and less impurities.
2. The diazotization reaction of the application is not needed to be carried out at low temperature, and is generally carried out at-5 ℃, and the application has the advantages of low energy consumption, short reaction time, high productivity, stable process (stable yield and purity) at 40-60 ℃.
3. According to the application, the diazotization reaction sodium nitrite solution and the sulfanilamide hydrochloric acid solution enter the reaction tank, flow into the reduction tank from the discharge port, and are simultaneously fed and discharged, and the reaction time and the temperature are controllable. Avoiding the occurrence of the phenomena of rapid foaming and slow discoloration and decomposition of sodium nitrite solution in the traditional process when the sodium nitrite solution is dripped into sulfanilamide hydrochloric acid.
4. The application pulps the crude product of the p-sulfonamide phenylhydrazine hydrochloride in hot absolute ethyl alcohol, which is favorable for removing organic impurities and pigments and has higher product purity.
Drawings
FIG. 1 is a process flow diagram of example 1 of the present application;
FIG. 2 shows a reaction apparatus of examples and comparative examples of the present application;
FIG. 3 is a liquid phase diagram of example 1 of the present application.
1. A sulfanilamide hydrochloric acid solution overhead tank; 2. a sodium nitrite solution overhead tank; 3. a sodium nitrite solution flowmeter; 4. a sulfanilamide hydrochloric acid solution flowmeter; 5. diazotizing a reaction tank; 6. a reduction tank.
Detailed Description
In order to make the objects, technical solutions and advantages of the present application more apparent, the technical solutions in the embodiments of the present application will be clearly and completely described in the following in conjunction with the embodiments of the present application. It will be apparent to those skilled in the art that the examples are merely to aid in understanding the application and are not to be construed as a specific limitation thereof. All other embodiments, which can be made by those skilled in the art based on the embodiments of the application without making any inventive effort, are intended to be within the scope of the application.
The examples of the present application are implemented on the premise of the technical scheme of the present application, and detailed implementation modes and processes are given, but the protection scope of the present application is not limited to the following examples, in which the process parameters of specific conditions are not noted, and generally according to conventional conditions.
The endpoints of the ranges and any values disclosed in the present application are not limited to the precise range or value, and the range or value should be understood to include values close to the range or value. For numerical ranges, one or more new numerical ranges may be obtained in combination with each other between the endpoints of each range, between the endpoint of each range and the individual point value, and between the individual point values, and are to be considered as specifically disclosed in the present application.
In the present application, all values relating to the amounts of the components are "parts by weight" throughout unless specified and/or indicated otherwise. The process parameters for the specific conditions not noted in the examples below are generally as usual.
The following is a further detailed description of a method of preparing a p-sulfonamide phenylhydrazine hydrochloride according to the present application by way of example, which is given only to illustrate the present application and not to limit the scope of the present application. The examples provided below may be used as a basis for further modifications and applications by those of ordinary skill in the art and are not intended to limit the scope of the application in any way.
The preparation methods of p-sulfonamide phenylhydrazine hydrochloride provided in the following examples and comparative examples were carried out in a reaction apparatus shown in fig. 2.
Example 1
The embodiment provides a preparation method of p-sulfonamide phenylhydrazine hydrochloride, the process flow chart is shown in figure 1, and the preparation method specifically comprises the following steps:
(1) 200kg of sodium nitrite is put into a sodium nitrite solution overhead tank 2, and water is added and stirred to obtain a sodium nitrite solution with the mass content of 20%;
400kg of sulfanilamide and 800kg of concentrated hydrochloric acid with the mass fraction of 36% are put into a sulfanilamide hydrochloric acid solution overhead tank 1, water is added and stirring is carried out, and a sulfanilamide hydrochloric acid solution (the solution contains 20% of sulfanilamide and 14.4% of hydrochloric acid by mass) is obtained.
(2) Firstly, opening a sodium nitrite solution flowmeter 3, after 3 seconds, opening a sulfanilamide hydrochloric acid solution flowmeter 4, opening saline water to control temperature, and adjusting the sodium nitrite solution and the sulfanilamide hydrochloric acid solutionThe flow rates of (a) are respectively 0.63m 3 /h and 1.25m 3 /h；
After 4min, the reaction solution reaches a discharge hole, a starch-potassium iodide solution is used for measuring the end point of the reaction solution at the outlet of the diazonium salt solution, the color of the reaction solution is changed into blue, pH test paper with the pH value of 0.5-5.0 is used for measuring the acidity, and the pH value at the outlet of the diazotization reaction tank is controlled to be 1.0-1.5;
in the diazotization reaction tank 5, the temperature is controlled at 50 ℃; the diazotisation reaction time was 4min.
(3) After the diazotization reaction is completed, the diazonium salt solution in the diazotization reaction tank 5 is pumped into the reduction tank 6 to perform a high-temperature reduction reaction. In the reduction reaction, 3045kg of sodium sulfite solution (the mass fraction of the sodium sulfite solution is 25%, the molar ratio of sodium sulfite in the sodium sulfite solution to sulfanilamide added in the step (1) is 2.6:1) is added, the reaction temperature is controlled to be 90 ℃, the reaction time is 1h, and the pH value is regulated to 6-7 by introducing ammonia.
(4) After the completion of the reduction reaction, 1000kg of 36% by mass hydrochloric acid solution was added at 1.0m 3 The reaction mixture/h was fed into the reduction tank 6, and the hydrolysis reaction was carried out at 90℃for 3 hours.
(5) After the hydrolysis reaction is finished, 1200kg of 36% hydrochloric acid solution is continuously added and stirred for 20min at 90 ℃, then the temperature is reduced to 25 ℃, the average cooling rate is 0.2 ℃/min, and the obtained solid is p-sulfonamide phenylhydrazine hydrochloride solid.
(6) Adding the obtained p-sulfonamide phenylhydrazine hydrochloride solid into absolute ethyl alcohol, pulping, wherein the mass ratio of the absolute ethyl alcohol to the sulfanilamide added in the step (1) is 1:5, and the pulping temperature is 80 ℃ and the pulping time is 20min.
(7) After pulping, centrifuging and drying at 50 ℃ to obtain the p-sulfonamide phenylhydrazine hydrochloride.
In this example, the yield of p-sulfonamide phenylhydrazine hydrochloride was 90%, and the purity of p-sulfonamide phenylhydrazine hydrochloride was 99.86% as measured by UltiMate 3000-type high performance liquid chromatography, as shown in FIG. 3.
Example 2
The embodiment provides a preparation method of p-sulfonamide phenylhydrazine hydrochloride, which comprises the following steps:
this example is different from example 1 in that the slurried solution in step (6) is isopropyl alcohol, and the rest of the steps are the same as in example 1.
In this example, the yield of p-sulfonamide phenylhydrazine hydrochloride was 90.1% and the purity was 99.84%.
Example 3
The embodiment provides a preparation method of p-sulfonamide phenylhydrazine hydrochloride, which comprises the following steps:
this example is different from example 1 in that the flow rate of the sodium nitrite solution in the step (2) is 0.5m 3 And/h, the flow rate of the sulfanilic acid solution is 1.0m 3 The diazotization reaction time was 5min, and the other steps were the same as in example 1.
In this example, the yield of p-sulfonamide phenylhydrazine hydrochloride was 90.3% and the purity was 99.88%.
Comparative example 1
The comparative example provides a preparation method of p-sulfonamide phenylhydrazine hydrochloride, which comprises the following steps:
this comparative example is different from example 1 in that the temperature of the diazotization reaction in step (2) is 5℃and the other steps are the same as in example 1.
In this comparative example, the yield of p-sulfonamide phenylhydrazine hydrochloride was 86% and the purity was 96.52%.
Comparative example 2
The comparative example provides a preparation method of p-sulfonamide phenylhydrazine hydrochloride, which comprises the following steps:
the difference between this comparative example and example 1 is that the impurity removal is performed by using purified water in step (6), specifically: adding the obtained solid p-sulfonamide phenylhydrazine hydrochloride into purified water (the mass ratio of sulfonamide to purified water is 1:0.5), dissolving at 70 ℃ at high temperature, and cooling to 25 ℃. The rest of the procedure was the same as in example 1.
In this comparative example, the yield of p-sulfonamide phenylhydrazine hydrochloride was 50% and the purity was 99.45%.
Comparative example 3
The comparative example provides a preparation method of p-sulfonamide phenylhydrazine hydrochloride, which comprises the following steps:
this comparative example was different from example 1 in that the temperature of the reduction reaction in step (3) was 70℃and the rest of the steps were the same as in example 1.
In this comparative example, the yield of p-sulfonamide phenylhydrazine hydrochloride was 85% and the purity was 98.78%.
Comparative example 4
The comparative example provides a preparation method of p-sulfonamide phenylhydrazine hydrochloride, which comprises the following steps:
the comparative example was different from example 1 in that the amount of hydrochloric acid solution added in step (4) was 400kg, and the other steps were the same as in example 1.
In this comparative example, the yield of p-sulfonamide phenylhydrazine hydrochloride was 78% and the purity was 81.23%.
Comparative example 5
The comparative example provides a preparation method of p-sulfonamide phenylhydrazine hydrochloride, which comprises the following steps:
the comparative example was different from example 1 in that the amount of hydrochloric acid solution added in step (5) was 300kg, and the other steps were the same as in example 1.
In this comparative example, the yield of p-sulfonamide phenylhydrazine hydrochloride was 35% and the purity was 99.68%.
Comparative example 6
The comparative example provides a preparation method of p-sulfonamide phenylhydrazine hydrochloride, which comprises the following steps:
this comparative example was different from example 1 in that the amount of hydrochloric acid solution added in step (5) was 1600kg, and the other steps were the same as in example 1.
In this comparative example, the yield of p-sulfonamide phenylhydrazine hydrochloride was 84% and the purity was 99.56%.
Comparative example 7
The comparative example provides a preparation method of p-sulfonamide phenylhydrazine hydrochloride, which comprises the following steps:
this comparative example is compared with example 1The difference is that the diazotization is carried out in the step (2) by adopting a tubular reaction, the tubular product 316L, the tube diameter DN32 and the tube length 25m, and the flow rates of the sodium nitrite solution and the sulfanilic acid solution are respectively 0.096m 3 /h and 0.204m 3 And/h, reaction time 4min. The rest of the procedure was the same as in example 1.
In this comparative example, the yield of p-sulfonamide phenylhydrazine hydrochloride was 89.8% and the purity was 99.23%.
467kg of p-sulfonamide phenylhydrazine hydrochloride was produced by the preparation method of example 1 and comparative example 7, example 1 required 1.6 hours and comparative example 7 required 9.8 hours. It can be seen that the production time of p-sulfonamide phenylhydrazine hydrochloride using comparative example 7 is significantly increased, and the production yield of p-sulfonamide phenylhydrazine hydrochloride is significantly reduced.
Comparative example 8
The comparative example provides a preparation method of p-sulfonamide phenylhydrazine hydrochloride, which comprises the following steps: in comparison with example 1, the reaction solution reached the discharge port after 10 minutes, and the time for the reaction solution to reach the discharge port was controlled by adjusting the flow rate. The rest of the procedure was the same as in example 1.
In this comparative example, the yield of p-sulfonamide phenylhydrazine hydrochloride was 84% and the purity was 94.58%.
The foregoing description of the preferred embodiments of the application is not intended to limit the application to the particular embodiments disclosed, but on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the application as defined by the appended claims.
Claims (10)
1. The preparation method of the p-sulfonamide phenylhydrazine hydrochloride is characterized by comprising the following steps of:
mixing a nitrite solution and a sulfanilamide hydrochloride solution, and sequentially carrying out diazotization reaction, reduction reaction, hydrolysis reaction and salification reaction to obtain p-sulfonamide phenylhydrazine hydrochloride;
in the diazotization reaction step, the reaction temperature is 40-60 ℃;
in the diazotization reaction step, the sulfanilamide hydrochloric acid solution and nitrite enter the bottom of a reaction kettle, and under the stirring action, the feed liquid turns upwards from the bottom to reach a discharge hole, so that the generated diazonium salt enters a reduction tank.
2. The method for preparing p-sulfonamide phenylhydrazine hydrochloride according to claim 1, wherein the sulfanilamide hydrochloride solution and the nitrite enter the bottom of the reaction kettle at the same time or the sulfanilamide hydrochloride solution enters the bottom of the reaction kettle for 2-5 seconds later than the sodium nitrite enters the bottom of the reaction kettle.
3. The method for producing p-sulfonylphenylhydrazine hydrochloride according to claim 1, wherein in the diazotizing step, the reaction time is 3 to 5min;
and/or in the step of reduction reaction, the temperature of the reduction reaction is 80-100 ℃, and the pH environment of the reduction reaction is 6-7.
4. The method for preparing p-sulfonamide phenylhydrazine hydrochloride according to claim 1, wherein in the hydrolysis reaction step, a hydrochloric acid solution is added for reaction, and the mass ratio of the hydrochloric acid solution to the sulfonamide is (2-4): 1, a step of;
and/or, in the salification reaction step, adding hydrochloric acid solution for stirring reaction, wherein the mass ratio of the hydrochloric acid solution to the sulfanilamide is (1.5-3.5): 1.
5. the method for producing p-sulfonylphenylhydrazine hydrochloride according to claim 1, wherein in the diazotizing step, the flow rate of the sodium nitrite solution into the diazotizing pot is 0.5 to 1.0m 3 /h；
And/or the flow rate of the sulfanilamide hydrochloric acid solution entering the diazotization reaction tank is 1-2m 3 /h；
And/or the pH value of the diazonium salt solution obtained after the diazotization reaction is finished is between 1.0 and 1.5.
6. The method for preparing p-sulfonamide phenylhydrazine hydrochloride according to claim 1, wherein the mass content of nitrite in the nitrite solution is 18-21%;
and/or, in the sulfanilamide hydrochloric acid solution, the mass content of sulfanilamide is 15-23%, and the mass content of HCl is 10.8-16.6%;
and/or the mass fraction of the hydrochloric acid is 35-36.5%;
and/or the nitrite comprises one of sodium nitrite and potassium nitrite, preferably sodium nitrite.
7. The method for producing p-sulfonylphenylhydrazine hydrochloride according to claim 1, wherein in the step of reduction reaction, the time of the reduction reaction is 1 to 2 hours.
During the reduction reaction, adding a reducing agent;
and/or the reducing agent is sodium sulfite solution;
and/or the mass fraction of the sodium sulfite aqueous solution is 25-33%;
and/or, the molar ratio of the sulfanilamide to the sodium sulfite in the sodium sulfite solution is 1: (2.6-4);
in the reduction reaction step, the mode of regulating the pH value comprises adding sodium hydroxide, sodium carbonate, ammonia water or introducing ammonia gas.
8. A process for the preparation of p-sulfonamide phenylhydrazine hydrochloride according to claim 1, wherein,
in the hydrolysis step, the addition rate of the hydrochloric acid solution is 0.8-1.2m 3 /h；
And/or the mass fraction of the hydrochloric acid solution is 35-36.5%;
the temperature of the hydrolysis reaction is 80-100 ℃;
and/or the hydrolysis reaction time is 3-5h;
the temperature of the salification reaction is 80-100 ℃;
and/or the salification reaction time is 10-20min;
and/or the mass fraction of the hydrochloric acid solution added in the salification reaction is 35-36.5%;
cooling after the salification reaction is finished;
and/or the average cooling rate is 0.1-1 ℃/min;
and/or the temperature after the temperature reduction is 15-25 ℃.
9. The method for preparing p-sulfonamide phenylhydrazine hydrochloride according to claim 1, further comprising the steps of refining, centrifuging and drying after the salifying reaction;
in the refining step, the solid p-sulfonamide phenylhydrazine hydrochloride is pulped.
The beating temperature is 60-80 ℃ and the beating time is 10-20min;
and/or the beating adopts an alcohol solvent, wherein the alcohol solvent comprises one of absolute ethyl alcohol, methanol and isopropanol;
and/or, the mass ratio of the sulfanilamide to the absolute ethyl alcohol is 1: (5-8);
and/or the drying temperature is 50-60 ℃.
10. A p-sulfonamide phenylhydrazine hydrochloride, characterized in that it is obtained from the process for the preparation of p-sulfonamide phenylhydrazine hydrochloride according to any of claims 1 to 9.
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