CN117105825A - Synthesis method of celecoxib intermediate p-hydrazino benzenesulfonamide hydrochloride - Google Patents
Synthesis method of celecoxib intermediate p-hydrazino benzenesulfonamide hydrochloride Download PDFInfo
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- IKEURONJLPUALY-UHFFFAOYSA-N 4-hydrazinylbenzenesulfonamide;hydron;chloride Chemical compound [Cl-].NS(=O)(=O)C1=CC=C(N[NH3+])C=C1 IKEURONJLPUALY-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 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 title claims abstract description 18
- 229960000590 celecoxib Drugs 0.000 title claims abstract description 17
- 238000001308 synthesis method Methods 0.000 title claims abstract description 5
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims abstract description 104
- 239000000243 solution Substances 0.000 claims abstract description 73
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 70
- 238000006243 chemical reaction Methods 0.000 claims abstract description 62
- 235000010288 sodium nitrite Nutrition 0.000 claims abstract description 52
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 claims abstract description 45
- 239000007787 solid Substances 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 19
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims abstract description 18
- 239000012535 impurity Substances 0.000 claims abstract description 11
- 230000020477 pH reduction Effects 0.000 claims abstract description 11
- 235000010265 sodium sulphite Nutrition 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 238000006193 diazotization reaction Methods 0.000 claims abstract description 7
- 238000002425 crystallisation Methods 0.000 claims abstract description 4
- 230000008025 crystallization Effects 0.000 claims abstract description 4
- 230000009467 reduction Effects 0.000 claims abstract description 4
- 239000007864 aqueous solution Substances 0.000 claims abstract description 3
- 238000005086 pumping Methods 0.000 claims abstract 2
- 229940124530 sulfonamide Drugs 0.000 claims description 29
- 230000002194 synthesizing effect Effects 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- XZMIAZCXISFPEJ-UHFFFAOYSA-N 4-aminobenzenesulfonamide;hydrochloride Chemical compound Cl.NC1=CC=C(S(N)(=O)=O)C=C1 XZMIAZCXISFPEJ-UHFFFAOYSA-N 0.000 claims 1
- 230000035484 reaction time Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 16
- 238000001816 cooling Methods 0.000 description 8
- 239000012954 diazonium Substances 0.000 description 8
- 150000001989 diazonium salts Chemical class 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 229950000244 sulfanilic acid Drugs 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 230000008859 change Effects 0.000 description 7
- 239000012295 chemical reaction liquid Substances 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- 239000007791 liquid phase Substances 0.000 description 7
- 230000008569 process Effects 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 238000007599 discharging Methods 0.000 description 6
- 238000011010 flushing procedure Methods 0.000 description 6
- 239000003507 refrigerant Substances 0.000 description 6
- 230000001105 regulatory effect Effects 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 239000000463 material Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 208000032023 Signs and Symptoms Diseases 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- GNKZMNRKLCTJAY-UHFFFAOYSA-N 4'-Methylacetophenone Chemical compound CC(=O)C1=CC=C(C)C=C1 GNKZMNRKLCTJAY-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- VNQMMBHDIDLJEZ-UHFFFAOYSA-N 2-hydrazinylbenzenesulfonamide;hydrochloride Chemical compound Cl.NNC1=CC=CC=C1S(N)(=O)=O VNQMMBHDIDLJEZ-UHFFFAOYSA-N 0.000 description 1
- 229910000619 316 stainless steel Inorganic materials 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- STSCVKRWJPWALQ-UHFFFAOYSA-N TRIFLUOROACETIC ACID ETHYL ESTER Chemical compound CCOC(=O)C(F)(F)F STSCVKRWJPWALQ-UHFFFAOYSA-N 0.000 description 1
- QCWXUUIWCKQGHC-UHFFFAOYSA-N Zirconium Chemical compound [Zr] QCWXUUIWCKQGHC-UHFFFAOYSA-N 0.000 description 1
- 208000005298 acute pain Diseases 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229910000856 hastalloy Inorganic materials 0.000 description 1
- 239000011344 liquid material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 238000013021 overheating Methods 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229910052726 zirconium Inorganic materials 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
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/42—Separation; Purification; Stabilisation; Use of additives
- C07C303/44—Separation; Purification
-
- 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
- C07C311/38—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 having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
- C07C311/39—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 having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a synthesis method of celecoxib intermediate p-hydrazino benzene sulfonamide hydrochloride, which belongs to the technical field of drug intermediate synthesis, and specifically comprises the steps of taking dilute hydrochloric acid as a solvent, firstly pumping into a dynamic tubular reactor, then respectively adding p-amino benzene sulfonamide solid and sodium nitrite solution into the dynamic tubular reactor for diazotization reaction, transferring the reaction solution into sodium sulfite aqueous solution for reduction after reaction, and obtaining pure p-hydrazino benzene sulfonamide hydrochloride after acidification, impurity removal and crystallization. The method is safe and environment-friendly, and has the advantages of simple operation, short reaction time and high product purity.
Description
Technical Field
The invention belongs to the field of synthesis of pharmaceutical intermediates, and relates to a method for synthesizing p-hydrazino benzenesulfonamide hydrochloride by adopting a dynamic tubular reactor.
Background
Celecoxib, chemical name 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -pyrazol-1-yl ] benzenesulfonamide, english name: celecoxib for use in alleviating symptoms and signs of osteoarthritis, alleviating symptoms and signs of rheumatoid arthritis in adults, treating acute pain in adults, and alleviating symptoms and signs of ankylosing spondylitis.
The current synthesis method of celecoxib mainly comprises the following steps:
the method comprises the following steps:
condensing p-methylacetophenone and ethyl trifluoroacetate under alkaline condition to obtain a beta-diketone intermediate, then directly condensing and cyclizing the beta-diketone intermediate with p-hydrazinobenzenesulfonamide hydrochloride in ethanol, and recrystallizing the crude product to obtain the celecoxib product.
The second method is as follows:
the p-amino benzene sulfonamide is reduced after diazotization to obtain p-hydrazino benzene sulfonamide hydrochloride, and then a condensation reaction is carried out to obtain a celecoxib product.
In both synthetic methods of celecoxib, an important medical intermediate p-hydrazino benzene sulfonamide hydrochloride is used, namely the main raw material for producing celecoxib, and is also commonly used as pesticide, dye and medical intermediate, and the foreign name is: 4-hydroazene-1-sulfonamide hydrochloride, molecular formula: c (C) 6 H 9 N 3 O 2 S.HCl, molecular weight: 223.5, CAS number: 17852-52-7.
The chemical structural formula is shown as follows:
the prior specific process for synthesizing the intermediate takes p-aminobenzenesulfonamide as a raw material, takes hydrochloric acid solution as a solvent, and takes diazotization reaction with sodium nitrite, and then obtains the product p-hydrazinobenzenesulfonamide hydrochloride through reduction, acidification, impurity removal, filtration and crystallization.
Because the diazotization reaction releases heat very severely, intermediate diazonium salt is unstable and is easy to decompose, and the problem that diazonium salt is decomposed due to local overheating caused by unstable dropping speed of sodium nitrite in consideration of low-temperature operation conditions in a kettle-type reactor is also solved.
Patent CN 110872242 mentions that the reaction is completed in a short time with an effective concentration by controlling the feeding manner in a reaction kettle, the reaction temperature is required to be relatively mild, and meanwhile, the diazonium salt decomposition caused by overlong transfer operation time is avoided, and the yield of the product p-hydrazinobenzenesulfonamide hydrochloride is 87.9%. The method has harsh requirements, attention is paid to temperature change of the reaction kettle at any time, and the reaction time is long.
In the patent CN 107573266, a microchannel reactor is adopted to carry out the synthesis reaction of the hydrazinobenzene sulfonamide hydrochloride, and the process ensures the stability of the diazotization reaction by utilizing the efficient heat and mass transfer effect of the microchannel reactor, and the product yield is 86.2%. However, the microchannel reactor is easy to be blocked, only the solution is allowed to pass through, the raw materials are required to be dissolved in advance, the liquid holdup of the microchannel reactor is only about two thousandths of that of a conventional reaction kettle, and the microchannel reactor is not suitable for large-scale industrial production.
The traditional process is carried out in a kettle type reactor, the reaction temperature is not accurately controlled, the stirring degree of the reaction is not uniform, the generated diazonium salt cannot be separated out in time in the reaction kettle and is continuously reacted with sodium nitrite, and slow decomposition of the diazonium salt is promoted, so that the preparation process which is high in efficiency, safety, good in yield, high in purity and suitable for large-scale industrial production is urgently required to be developed.
Disclosure of Invention
The invention provides a method for synthesizing p-hydrazinobenzenesulfonamide hydrochloride by adopting a dynamic tubular reactor aiming at the defects in the prior art. The invention takes dilute hydrochloric acid as solvent and pumps into a dynamic tubular reactor, then the solid para-aminobenzene sulfonamide and sodium nitrite solution are respectively added into the dynamic tubular reactor for diazotization reaction, after the reaction is finished, the reaction solution is transferred into sodium sulfite aqueous solution for reduction, and then the pure para-hydrazino benzene sulfonamide hydrochloride is obtained after acidification, impurity removal and crystallization.
The reaction residence time of the dynamic tubular reactor is 1-5 min, preferably 2.8-3.5 min, the reaction temperature is-15-5 ℃, preferably-10 ℃ and the reaction pressure is 0.1-0.5 kpa.
The mass ratio of hydrochloric acid to water in the dilute hydrochloric acid solvent is 1.0:1.2 to 1.8, preferably 1.0:1.5, the mass ratio of the sulfanilic acid amide to the dilute hydrochloric acid is 1:3.5-6.0, and is preferably 1.0:5.0.
the mass ratio of sodium nitrite to water in the sodium nitrite solution is 1:1.3 to 1.6, preferably 1:1.45.
the sulfanilamide is preferably solid in feed, so that the dissolution process is avoided, the sulfanilamide and the dilute hydrochloric acid solvent are mixed in a reactor, and meanwhile, sodium nitrite solution is introduced for reaction.
The molar ratio of the sulfanilic acid amide to the sodium nitrite which is introduced into the dynamic tubular reactor is 1.0:1.0 to 1..05, preferably 1.0:1.0 to 1.02.
The mass flow rate of the para-aminobenzene sulfonamide is 8-15 g/min, preferably 10g/min, the volume flow rate of the dilute hydrochloric acid solution is 40-60 mL/min, preferably 50mL/min, and the volume flow rate of the sodium nitrite is 6-12 mL/min, preferably 7.5-8.2 mL/min.
The invention has the following advantages:
(1) The raw material p-aminobenzene sulfonamide can be directly and solid fed, and can be continuously fed, so that the dissolution process is avoided, the process flow is reduced, and the efficiency is improved.
(2) The reaction selectivity is good, the product yield is high and reaches 91.3%, the purity is 98.6%, the rapid and effective mixing reaction of reactants is realized by setting reasonable reaction conditions and adopting proper reaction equipment, the residence time and the reaction temperature are accurately controlled, and the reaction conversion rate and the selectivity are improved.
(3) The dynamic tubular reactor has no back mixing, and can timely separate out generated diazonium salt, thereby effectively avoiding side reaction of diazonium salt and preventing diazonium salt from decomposing.
(4) The reaction time is obviously improved, the original reaction time of 2-3 hours is reduced to 2-5min, the reaction efficiency is obviously improved, the output of products in unit time is improved, and the large-scale industrial production can be carried out.
Detailed Description
The dynamic tubular reactor adopted by the invention is a dynamic tubular reactor of Shandong micro-well chemical engineering Co., ltd, the material of the mixed reaction module is 316L, hastelloy and zirconium, the liquid holdup is 500mL, and the liquid material feeding mode of the dynamic tubular reactor is plunger pump driving continuous feeding. The reactor itself includes a reaction unit, a pressure-stabilizing heat exchange unit and a control unit. In the practical application process, a material collecting back pressure system is also needed in cooperation with a material control system, a temperature control system, a gas control system and a material collecting back pressure system.
Example 1:
(1) The sulfanilamide is fed at a solid feed inlet, the hydrochloric acid solution and the sodium nitrite solution are fed by a fine feed pump, the mass flow rate of sulfanilamide is 10g/min, the volume flow rate of hydrochloric acid is 50mL/min, and the volume flow rate of sodium nitrite is 6.5mL/min. Wherein the mass fraction of the sodium nitrite solution is 65%, and the molar ratio of the sulfanilic acid amide to the sodium nitrite is 1:1.01.
(2) Setting the temperature value of the temperature control integrated machine, and setting the reaction temperature to-10 ℃ for precooling. The reactor speed was 260rpm. And opening a flow regulating valve of the refrigerant inlet pipeline, starting to regulate the temperature of the pipeline, flushing the pipeline by using dilute hydrochloric acid solution after the temperature of the equipment is reduced to a set value, and discharging washing liquid at a lower outlet.
(3) After precooling of each area in the device is completed, starting a dilute hydrochloric acid solution pump for 1min, observing the change of the temperature in the reactor, adding the sulfanilamide solid when the temperature is stabilized at a set value, and simultaneously starting a sodium nitrite solution pump, wherein sulfanilamide and sodium nitrite are fed according to the proportion. Wherein the reaction temperature of the dynamic tubular reactor is-10 ℃, the residence time is 3min, and the reaction pressure is 0.3KPa.
(4) And 3min later, taking the reaction liquid from the outlet for liquid phase test, wherein the conversion rate of the p-aminobenzenesulfonamide is 100%.
(5) Directly introducing the reaction solution into sodium sulfite solution, heating to 85 ℃ after reacting for 30min, adding hydrochloric acid solution for acidification, adding active carbon for impurity removal, finally cooling and crystallizing, and suction filtering to obtain white solid, wherein the yield is 94.3%, and the purity is 99.2%.
Example 2:
(1) The sulfanilamide is fed at a solid feed inlet, the hydrochloric acid solution and the sodium nitrite solution are fed by a fine feed pump, the mass flow rate of sulfanilamide is 10g/min, the volume flow rate of hydrochloric acid is 50mL/min, and the volume flow rate of sodium nitrite is 6mL/min. Wherein the mass fraction of the sodium nitrite solution is 65%, and the molar ratio of the sulfanilic acid amide to the sodium nitrite is 1:1.0.
(2) Setting the temperature value of the temperature control integrated machine, and setting the reaction temperature to-10 ℃ for precooling. The reactor speed was 260rpm. And opening a flow regulating valve of the refrigerant inlet pipeline, starting to regulate the temperature of the pipeline, flushing the pipeline by using dilute hydrochloric acid solution after the temperature of the equipment is reduced to a set value, and discharging washing liquid at a lower outlet.
(3) After precooling of each area in the device is completed, starting a dilute hydrochloric acid solution pump for 1min, observing the change of the temperature in the reactor, adding the sulfanilamide solid when the temperature is stabilized at a set value, and simultaneously starting a sodium nitrite solution pump, wherein sulfanilamide and sodium nitrite are fed according to the proportion. Wherein the reaction temperature of the dynamic tubular reactor is-10 ℃, the residence time is 3min, and the reaction pressure is 0.3KPa.
(4) And 3min later, taking the reaction liquid from the outlet for liquid phase test, wherein the conversion rate of the p-aminobenzenesulfonamide is 100%.
(5) Directly introducing the reaction solution into sodium sulfite solution, heating to 85 ℃ after reacting for 30min, adding hydrochloric acid solution for acidification, adding active carbon for impurity removal, finally cooling and crystallizing, and suction filtering to obtain white solid, wherein the yield is 94.6%, and the purity is 99.1%.
Example 3:
(1) The sulfanilamide is fed at a solid feed inlet, the hydrochloric acid solution and the sodium nitrite solution are fed by a fine feed pump, the mass flow rate of sulfanilamide is 10g/min, the volume flow rate of hydrochloric acid is 50mL/min, and the volume flow rate of sodium nitrite is 7.5mL/min. Wherein the mass fraction of the sodium nitrite solution is 65%, and the molar ratio of the sulfanilic acid amide to the sodium nitrite is 1:1.1.
(2) Setting the temperature value of the temperature control integrated machine, and setting the reaction temperature to-10 ℃ for precooling. The reactor speed was 260rpm. And opening a flow regulating valve of the refrigerant inlet pipeline, starting to regulate the temperature of the pipeline, flushing the pipeline by using dilute hydrochloric acid solution after the temperature of the equipment is reduced to a set value, and discharging washing liquid at a lower outlet.
(3) After precooling of each area in the device is completed, starting a dilute hydrochloric acid solution pump for 1min, observing the change of the temperature in the reactor, adding the sulfanilamide solid when the temperature is stabilized at a set value, and simultaneously starting a sodium nitrite solution pump, wherein sulfanilamide and sodium nitrite are fed according to the proportion. Wherein the reaction temperature of the dynamic tubular reactor is-10 ℃, the residence time is 3min, and the reaction pressure is 0.3KPa.
(4) And 3min later, taking the reaction liquid from the outlet for liquid phase test, wherein the conversion rate of the p-aminobenzenesulfonamide is 99%.
(5) Directly introducing the reaction solution into sodium sulfite solution, heating to 85 ℃ after reacting for 30min, adding hydrochloric acid solution for acidification, adding active carbon for impurity removal, finally cooling and crystallizing, and suction filtering to obtain white solid, wherein the yield is 94.3%, and the purity is 99.7%.
Example 4:
(1) The sulfanilamide is fed at a solid feed inlet, the hydrochloric acid solution and the sodium nitrite solution are fed by a fine feed pump, the mass flow rate of sulfanilamide is 10g/min, the volume flow rate of hydrochloric acid is 50mL/min, and the volume flow rate of sodium nitrite is 6.5mL/min. Wherein the mass fraction of the sodium nitrite solution is 65%, and the molar ratio of the sulfanilic acid amide to the sodium nitrite is 1:1.01.
(2) Setting the temperature value of the temperature control integrated machine, and setting the reaction temperature to-15 ℃ for precooling. The reactor speed was 260rpm. And opening a flow regulating valve of the refrigerant inlet pipeline, starting to regulate the temperature of the pipeline, flushing the pipeline by using dilute hydrochloric acid solution after the temperature of the equipment is reduced to a set value, and discharging washing liquid at a lower outlet.
(3) After precooling of each area in the device is completed, starting a dilute hydrochloric acid solution pump for 1min, observing the change of the temperature in the reactor, adding the sulfanilamide solid when the temperature is stabilized at a set value, and simultaneously starting a sodium nitrite solution pump, wherein sulfanilamide and sodium nitrite are fed according to the proportion. Wherein the reaction temperature of the dynamic tubular reactor is-15 ℃, the residence time is 3min, and the reaction pressure is 0.3KPa.
(4) And 3min later, taking the reaction liquid from the outlet for liquid phase test, wherein the conversion rate of the p-aminobenzenesulfonamide is 83%.
(5) Directly introducing the reaction solution into sodium sulfite solution, heating to 85 ℃ after reacting for 30min, adding hydrochloric acid solution for acidification, adding active carbon for impurity removal, finally cooling and crystallizing, and suction filtering to obtain white solid with the yield of 92.1% and the purity of 99.3%.
Example 5:
(1) The sulfanilamide is fed at a solid feed inlet, the hydrochloric acid solution and the sodium nitrite solution are fed by a fine feed pump, the mass flow rate of sulfanilamide is 5g/min, the volume flow rate of hydrochloric acid is 25mL/min, and the volume flow rate of sodium nitrite is 3.5mL/min. Wherein the mass fraction of the sodium nitrite solution is 65%, and the molar ratio of the sulfanilic acid amide to the sodium nitrite is 1:1.01.
(2) Setting the temperature value of the temperature control integrated machine, and setting the reaction temperature to-10 ℃ for precooling. The reactor speed was 260rpm. And opening a flow regulating valve of the refrigerant inlet pipeline, starting to regulate the temperature of the pipeline, flushing the pipeline by using dilute hydrochloric acid solution after the temperature of the equipment is reduced to a set value, and discharging washing liquid at a lower outlet.
(3) After precooling of each area in the device is completed, starting a dilute hydrochloric acid solution pump for 1min, observing the change of the temperature in the reactor, adding the sulfanilamide solid when the temperature is stabilized at a set value, and simultaneously starting a sodium nitrite solution pump, wherein sulfanilamide and sodium nitrite are fed according to the proportion. Wherein the reaction temperature of the dynamic tubular reactor is-10 ℃, the residence time is 6min, and the reaction pressure is 0.3KPa.
(4) And after 6min, taking the reaction liquid from the outlet for liquid phase test, wherein the conversion rate of the p-aminobenzenesulfonamide is 99%.
(5) Directly introducing the reaction solution into sodium sulfite solution, heating to 85 ℃ after reacting for 30min, adding hydrochloric acid solution for acidification, adding active carbon for impurity removal, finally cooling and crystallizing, and suction filtering to obtain white solid with the yield of 93.7% and the purity of 99.6%.
Comparative example 1:
adding 50g of sulfanilamide into a 1000mL three-neck flask, adding 150mL of water, mixing, stirring at room temperature, simultaneously dropwise adding 100g of hydrochloric acid solution, heating to 50 ℃ after the dripping is finished, cooling to-10 ℃ after the reaction liquid in the flask is fully dissolved, and dropwise adding NaNO with the mass fraction of 65% after stabilizing 2 35mL of solution, maintaining the temperature at-10 ℃ for 30min, stirring for 10min after the dripping, and then introducing the reaction solution into Na 2 SO 3 Reducing for 30min in the solution, heating to 95 ℃ after the reaction is finished, adding hydrochloric acid solution for acidification, removing impurities by using active carbon, cooling and crystallizing, and performing suction filtration to obtain white solid, wherein the yield is 82.7%, and the purity of the liquid phase is 97%.
Comparative example 2:
(1) The sulfanilamide is fed at a solid feed inlet, the hydrochloric acid solution and the sodium nitrite solution are fed by a fine feed pump, the mass flow rate of sulfanilamide is 50g/min, the volume flow rate of hydrochloric acid is 80mL/min, and the volume flow rate of sodium nitrite is 9.5mL/min. Wherein the mass fraction of the sodium nitrite solution is 65%, and the molar ratio of the sulfanilic acid amide to the sodium nitrite is 1:2.1.
(2) Setting the temperature value of the temperature control integrated machine, and setting the reaction temperature to minus 20 ℃ for precooling. The reactor speed was 370rpm. And opening a flow regulating valve of the refrigerant inlet pipeline, starting to regulate the temperature of the pipeline, flushing the pipeline by using dilute hydrochloric acid solution after the temperature of the equipment is reduced to a set value, and discharging washing liquid at a lower outlet.
(3) After precooling of each area in the device is completed, starting a dilute hydrochloric acid solution pump for 1min, observing the change of the temperature in the reactor, adding the sulfanilamide solid when the temperature is stabilized at a set value, and simultaneously starting a sodium nitrite solution pump, wherein sulfanilamide and sodium nitrite are fed according to the proportion. Wherein the reaction temperature of the dynamic tubular reactor is-20 ℃, the residence time is 120min, and the reaction pressure is 0.9KPa.
(4) And 3min later, taking the reaction liquid from the outlet for liquid phase test, wherein the conversion rate of the p-aminobenzenesulfonamide is 82%.
(5) Directly introducing the reaction solution into sodium sulfite solution, heating to 85 ℃ after reacting for 30min, adding hydrochloric acid solution for acidification, adding active carbon for impurity removal, finally cooling and crystallizing, and suction filtering to obtain white solid, wherein the yield is 37.3%, and the purity is 67.2%.
While the foregoing has been described in conjunction with the embodiments of the present invention, it will be apparent to those skilled in the art that many modifications and variations are possible without the need for inventive faculty.
Claims (7)
1. The synthesis method of celecoxib intermediate p-hydrazino benzenesulfonamide hydrochloride is characterized by comprising the following steps of:
pumping dilute hydrochloric acid as solvent into a dynamic tubular reactor, adding solid sulfanilamide and sodium nitrite solution into the dynamic tubular reactor respectively for diazotization, transferring the reaction solution into sodium sulfite aqueous solution for reduction after the reaction, and obtaining pure sulfanilamide hydrochloride after acidification, impurity removal and crystallization.
2. The method for synthesizing celecoxib intermediate p-hydrazino benzenesulfonamide hydrochloride according to claim 1, wherein the reaction residence time of the dynamic tubular reactor is 1-5 min, the reaction temperature is-15 to-5 ℃, and the reaction pressure is 0.1-0.5 kpa.
3. The method for synthesizing celecoxib intermediate p-hydrazinobenzenesulfonamide hydrochloride according to claim 1, wherein the mass ratio of hydrochloric acid to water in the dilute hydrochloric acid solvent is 1.0:1.2 to 1.8, and the mass ratio of the p-aminobenzene sulfonamide to the dilute hydrochloric acid is 1:3.5 to 6.0.
4. The method for synthesizing celecoxib intermediate p-hydrazino benzenesulfonamide hydrochloride according to claim 1, wherein the mass ratio of sodium nitrite to water in the sodium nitrite solution is 1:1.3 to 1.6.
5. The method for synthesizing celecoxib intermediate p-hydrazinobenzenesulfonamide hydrochloride according to claim 1, wherein the p-aminobenzenesulfonamide is a solid feed, wherein the p-aminobenzenesulfonamide and a dilute hydrochloric acid solvent are mixed in a dynamic tubular reactor, and simultaneously a sodium nitrite solution is introduced for reaction.
6. The method for synthesizing celecoxib intermediate p-hydrazinobenzenesulfonamide hydrochloride according to claim 1, wherein the molar ratio of p-aminobenzenesulfonamide to sodium nitrite is 1.0:1.0 to 1.05.
7. The method for synthesizing celecoxib intermediate p-hydrazinobenzenesulfonamide hydrochloride according to claim 1, wherein the mass flow rate of p-aminobenzenesulfonamide is 8-15 g/min, the volume flow rate of dilute hydrochloric acid solution is 40-60 mL/min, and the volume flow rate of sodium nitrite is 6-12 mL/min.
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