CN115850199B - Preparation method of high-purity sodium sulfaisoxazole - Google Patents
Preparation method of high-purity sodium sulfaisoxazole Download PDFInfo
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- NHUHCSRWZMLRLA-UHFFFAOYSA-N Sulfisoxazole Chemical compound CC1=NOC(NS(=O)(=O)C=2C=CC(N)=CC=2)=C1C NHUHCSRWZMLRLA-UHFFFAOYSA-N 0.000 title claims abstract description 34
- 229960000654 sulfafurazole Drugs 0.000 title claims abstract description 34
- 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 title claims abstract description 26
- 239000011734 sodium Substances 0.000 title claims abstract description 26
- 229910052708 sodium Inorganic materials 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 28
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 88
- 238000003756 stirring Methods 0.000 claims description 46
- 239000007787 solid Substances 0.000 claims description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 39
- 239000012065 filter cake Substances 0.000 claims description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 28
- 238000000967 suction filtration Methods 0.000 claims description 27
- 238000002425 crystallisation Methods 0.000 claims description 26
- 230000008025 crystallization Effects 0.000 claims description 26
- 229910052799 carbon Inorganic materials 0.000 claims description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- 238000001816 cooling Methods 0.000 claims description 21
- 239000003513 alkali Substances 0.000 claims description 20
- 239000007788 liquid Substances 0.000 claims description 20
- 238000010438 heat treatment Methods 0.000 claims description 18
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims description 17
- 239000000047 product Substances 0.000 claims description 16
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 15
- 230000001276 controlling effect Effects 0.000 claims description 15
- 239000012452 mother liquor Substances 0.000 claims description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- 230000001105 regulatory effect Effects 0.000 claims description 14
- UYMKPFRHYYNDTL-UHFFFAOYSA-N ethenamine Chemical compound NC=C UYMKPFRHYYNDTL-UHFFFAOYSA-N 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 10
- 239000010413 mother solution Substances 0.000 claims description 10
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 9
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 9
- 229960001330 hydroxycarbamide Drugs 0.000 claims description 9
- VKPQLZPZPYQFOK-UHFFFAOYSA-N 2-acetamidobenzenesulfonyl chloride Chemical compound CC(=O)NC1=CC=CC=C1S(Cl)(=O)=O VKPQLZPZPYQFOK-UHFFFAOYSA-N 0.000 claims description 7
- 235000019441 ethanol Nutrition 0.000 claims description 7
- 239000000463 material Substances 0.000 claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 238000001704 evaporation Methods 0.000 claims description 6
- 238000007664 blowing Methods 0.000 claims description 4
- 229960005404 sulfamethoxazole Drugs 0.000 claims description 4
- JLKIGFTWXXRPMT-UHFFFAOYSA-N sulphamethoxazole Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 JLKIGFTWXXRPMT-UHFFFAOYSA-N 0.000 claims description 4
- 238000007605 air drying Methods 0.000 claims description 3
- 238000004140 cleaning Methods 0.000 claims description 3
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 230000007935 neutral effect Effects 0.000 claims description 2
- 230000001376 precipitating effect Effects 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 1
- SKIVFJLNDNKQPD-UHFFFAOYSA-N sulfacetamide Chemical compound CC(=O)NS(=O)(=O)C1=CC=C(N)C=C1 SKIVFJLNDNKQPD-UHFFFAOYSA-N 0.000 claims 1
- 229960002673 sulfacetamide Drugs 0.000 claims 1
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 abstract description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 abstract description 3
- 239000000460 chlorine Substances 0.000 abstract description 3
- 229910052801 chlorine Inorganic materials 0.000 abstract description 3
- 231100000086 high toxicity Toxicity 0.000 abstract description 2
- GGZRVXCSRWTOME-UHFFFAOYSA-N pyridine;toluene Chemical compound C1=CC=NC=C1.CC1=CC=CC=C1 GGZRVXCSRWTOME-UHFFFAOYSA-N 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 11
- 150000001721 carbon Chemical group 0.000 description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- RHFWLPWDOYJEAL-UHFFFAOYSA-N 1,2-oxazol-3-amine Chemical compound NC=1C=CON=1 RHFWLPWDOYJEAL-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 238000002386 leaching Methods 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 241000251468 Actinopterygii Species 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- RJJDLPQZNANQDQ-UHFFFAOYSA-N 2,3-dichloropropanenitrile Chemical compound ClCC(Cl)C#N RJJDLPQZNANQDQ-UHFFFAOYSA-N 0.000 description 1
- GRDXCFKBQWDAJH-UHFFFAOYSA-N 4-acetamidobenzenesulfonyl chloride Chemical compound CC(=O)NC1=CC=C(S(Cl)(=O)=O)C=C1 GRDXCFKBQWDAJH-UHFFFAOYSA-N 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 241000252233 Cyprinus carpio Species 0.000 description 1
- 241001327682 Oncorhynchus mykiss irideus Species 0.000 description 1
- BEGKPPZBSJFKMI-UHFFFAOYSA-N [Na].O1N=CC=C1 Chemical compound [Na].O1N=CC=C1 BEGKPPZBSJFKMI-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000002531 positive electrospray ionisation time-of-flight mass spectrometry Methods 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention discloses a preparation method of high-purity sodium sulfaisoxazole, which takes pyridine toluene as a starting material to prepare the sodium sulfaisoxazole. The preparation method provided by the invention has the advantages of simple process steps, simple operation steps, removal of acrylonitrile and chlorine which are raw materials with high toxicity and danger, and higher product yield and purity. The invention can be used for production by common equipment without using high-risk process, and meanwhile, the intermediate of the invention is safer and more environment-friendly.
Description
Technical Field
The application relates to the technical field of organic synthesis, in particular to a preparation method of high-purity sodium sulfaisoxazole.
Background
Sodium sulfaisoxazole, an alias 3-p-aminobenzenesulfonamide isoxazole sodium salt, of formula: c 9H8N3NaO3 S. The sodium sulfaisoxazole is used for treating solitary fish, rainbow trout, solitary bacterial diseases of fragrant fish and carp, cold water diseases, cave diseases and the like.
At present, regarding the synthesis of sodium sulfaisoxazole, the synthesis of a key intermediate 3-amino isoxazole in the prior art needs to use a highly toxic product acrylonitrile and chlorine to prepare highly corrosive 2, 3-dichloropropionitrile, the process is a high-risk process, extremely high requirements are imposed on equipment and the process, a large amount of solvent is required for extracting the 3-amino isoxazole, and the environment is also stressed greatly. Therefore, there is a need to develop a new preparation method of sodium sulfaisoxazole.
Disclosure of Invention
The application aims to: aiming at the defects in the prior art, the application provides a novel preparation method of sodium sulfaisoxazole. The method can avoid the harm of the prior art and can obtain the sodium sulfaisoxazole with higher purity.
The technical scheme is as follows: the preparation method of the high-purity sodium sulfaisoxazole provided by the invention is carried out according to the following synthetic lines:
Specifically, in the step 1), vinylamine and tolylpyridine are put into a reaction bottle; adding acetamido benzene sulfonyl chloride in batches under the temperature of 25 ℃; after the material is fed, stirring and reacting at the temperature of 27-32 ℃, adding water after the reaction is finished, stirring, filtering after a large amount of white solid is separated out, and washing a filter cake to be neutral; air drying the filter cake at 50-60 ℃ to obtain intermediate I white solid;
Step 2), adding absolute ethyl alcohol and an intermediate I into a reaction bottle; heating to 40-45 ℃, and adding hydrobromic acid; controlling the temperature to be 40-45 ℃ and dividing NBS into batches in a reaction kettle, wherein the temperature in the reaction process is not more than 60 ℃; after NBS feeding is finished, controlling the temperature to be 50+/-5 ℃ for reaction;
Step 3) adding hydroxyurea into a reaction bottle, heating to above 75 ℃ and after reflux occurs, starting timing reaction, cooling the reaction liquid to 10 ℃ after the reaction is finished, starting timing crystallization, and controlling the temperature to 10+/-5 ℃ in the crystallization process; leaching, leaching with ethanol to obtain intermediate II white solid;
Step 4), adding an intermediate II, water and liquid alkali into a reaction bottle, and dissolving; stirring at the temperature of 60-75 ℃, cooling to 45-55 ℃ after the reaction is finished, and regulating the PH=8-10 by using concentrated hydrochloric acid; adding active carbon, stirring and suction filtering; cooling the mother solution to below 30 ℃, regulating the temperature to PH=4-5 by using concentrated hydrochloric acid, precipitating a large amount of white solid, and carrying out suction filtration; eluting a filter cake, and drying the filter cake by blowing at 70-80 ℃ for 8 hours to obtain white-like solid sulfaisoxazole;
Step 5) adding the sulfamethoxazole and water into a reaction bottle, heating to 65-75 ℃, adding liquid alkali, dissolving, and cleaning, wherein PH=9-10; stirring, adding active carbon, and suction filtering; evaporating part of water from the mother liquor, cooling to 0-10 ℃ and crystallizing; and (3) carrying out suction filtration, and carrying out blast drying on a filter cake at 60-70 ℃ to obtain a finished product of white solid sodium sulfaisoxazole, wherein mother liquor can be used for the next batch instead of a water jacket in the salifying process.
Specifically, the molar ratio of vinylamine, toluene, pyridine and ASC in the step 1) is: 1: 14-15: 6-7: 1.1 to 1.2; the weight ratio of vinylamine to water is: 1: 15-20.
Specifically, the step 2) is performed with intermediate I: hydrobromic acid: the molar ratio of NBS is: 1:0.1 to 0.2:1.1 to 1.3.
Specifically, the step 3) is intermediate I: the molar ratio of hydroxyurea is: 1:1 to 1.1.
Specifically, the weight ratio of 7.4% liquid alkali to intermediate II in the step 4) is: 7-8: 1, a step of; the hydrolysis temperature is 60-75 ℃.
Specifically, the molar ratio of the sulfaisoxazole to the sodium hydroxide in the step 5) is as follows: 1:1 to 1.05; .
Specifically, the liquid alkali in the step 5) is 30% liquid alkali.
Specifically, the content of the sodium sulfaisoxazole in the crystallization mother liquor in the step 5) is 40-60%, and the crystallization temperature is 0-10 ℃.
More specifically, an exemplary technical solution of the present invention is as follows:
Step 1), adding vinylamine and pyridine toluene into a reaction bottle; adding acetamido benzene sulfonyl chloride in batches under the temperature of 25 ℃; after the material is fed, stirring and reacting for 10 hours at the temperature of 27-32 ℃. After the completion of the reaction, 420g of water was added thereto, followed by stirring for 30 minutes, whereby a large amount of white solid was precipitated. Suction filtration is carried out, and filter cakes are washed to PH=7; and (3) drying the filter cake by blowing at 50-60 ℃ for 8 hours to obtain an intermediate I white solid.
Step 2), adding absolute ethyl alcohol and an intermediate I into a reverse reaction bottle; heating to 40-45 ℃, and adding hydrobromic acid; controlling the temperature to be 40-45 ℃ and dividing NBS into batches in a reaction kettle, wherein the temperature in the reaction process is not more than 60 ℃; after the NBS feeding is finished, controlling the temperature to be 50+/-5 ℃ for reacting for 0.5 hour;
step 3) adding hydroxyurea into a reaction bottle, heating to more than 75 ℃ and starting timing reaction for 2 hours after reflux occurs; after the reaction is finished, the temperature of the reaction solution is reduced to 10 ℃, then timing crystallization is started for 2 hours, and the temperature is controlled to be 10+/-5 ℃ in the crystallization process; suction filtration and leaching with a small amount of ethanol to obtain an intermediate II white solid.
Step 4), adding an intermediate II, water and 30% liquid alkali into a reaction bottle, and dissolving; preserving heat at 60-75 ℃ and stirring for 4 hours; after the reaction is finished, cooling to 45-55 ℃, and regulating the PH to 8-10 by using concentrated hydrochloric acid; adding active carbon, stirring for 20 minutes, and suction filtering; the mother liquor is cooled to below 30 ℃, then is regulated to PH=4-5 by concentrated hydrochloric acid, a large amount of white solid is precipitated, and suction filtration is carried out. The filter cake was rinsed with l water. And (3) drying the filter cake at 70-80 ℃ by blowing for 8 hours to obtain white solid-like sulfaisoxazole.
Step 5) adding the sulfamethoxazole and water into a reaction bottle, heating to 65-75 ℃, adding 30% liquid alkali, dissolving, and cleaning, wherein PH=9-10; stirring for 20 minutes, adding active carbon, and suction filtering; and (3) evaporating part of water from the mother liquor, and cooling to 0-10 ℃ for crystallization. And (3) carrying out suction filtration, and carrying out forced air drying on a filter cake at 60-70 ℃ for 8 hours to obtain a finished product of white solid sodium sulfaisoxazole, wherein mother liquor can be used for the next batch instead of a water jacket in the salifying process.
The beneficial effects are that: the preparation method provided by the invention has the advantages of simple process steps, simple operation steps, removal of acrylonitrile and chlorine which are raw materials with high toxicity and danger, and higher product yield and purity.
The invention can be used for production without using high-risk process (chlorination process), and the intermediate of the invention is safer and more environment-friendly.
The intermediate 3-amino isoxazole of the prior art has relatively low purity, so that part of impurities can be introduced into the next step, and even the final finished product. The intermediate of the invention has relatively high purity, less introduced impurities and relatively high purity of the final product.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of the product obtained in example 1.
FIG. 2 is a nuclear magnetic resonance spectrum of the product obtained in example 1.
FIG. 3 is a mass spectrum of the product obtained in example 1.
Detailed Description
The technical scheme of the present application is described in detail by examples below, but the scope of the present application is not limited to the examples.
Example 1:
10g of vinylamine is put into a 1000ml reaction bottle, and stirring is started; adding 330g of toluene and 120g of pyridine, and cooling; 67.7g of acetamido benzenesulfonyl chloride is added in batches below 25 ℃; after the material is fed, the temperature is kept at 27-32 ℃ and the reaction is stirred for 10 hours. After the completion of the reaction, 420g of water was added thereto, followed by stirring for 30 minutes, whereby a large amount of white solid was precipitated. Suction filtration is carried out, and filter cakes are washed to PH=7; the filter cake was air-dried at 50-60℃for 8 hours to give 58.7g of intermediate I as a white solid in 90.4% yield.
200G of absolute ethyl alcohol is put into a 1000ml reaction bottle, and stirring is started; then adding intermediate I40 g; heating to 40-45 ℃, and adding hydrobromic acid 3.3g of 0.0167mol percent 40 percent; 35.3g of NBS is added into the reaction kettle for 5 times, the temperature is 40-45 ℃ when NBS is added each time, and the temperature in the reaction process is not more than 60 ℃; after the NBS feeding is finished, controlling the temperature to be 50+/-5 ℃ for reacting for 0.5 hour;
12.7g of hydroxyurea is put into a reaction bottle, the temperature is raised to above 75 ℃ and after reflux occurs, the timing reaction is started for 2 hours; after the reaction is finished, the temperature of the reaction solution is reduced to 10 ℃, then timing crystallization is started for 2 hours, and the temperature is controlled to be 10+/-5 ℃ in the crystallization process; suction filtration, rinsing with a small amount of ethanol, and obtaining 39.1g of intermediate II white solid with the yield of 84.3%.
28.1G of intermediate II and 168.6g of water are put into a 2000ml reaction bottle, and 56.2g of 30% liquid alkali is added by stirring, so as to dissolve; heating to 70-75 ℃, preserving heat and stirring for 4 hours; after the reaction is finished, cooling to 45-55 ℃, and regulating the PH to 8-10 by using concentrated hydrochloric acid; adding 2.5g of active carbon, stirring for 20 minutes, and then carrying out suction filtration; the mother solution is cooled to below 30 ℃, then the pH value is regulated to be 4-5 by concentrated hydrochloric acid, a large amount of white solid is precipitated, and the mixture is stirred for 20 minutes and then is filtered. The filter cake was rinsed 3 times with 200ml of water. The filter cake was air-dried at 70-80℃for 8 hours to give 20.1g of an off-white solid. The purity was 99.20% and the molar yield was 83.9%.
Adding 20g of sulfamethoxazole into a 2000ml reaction bottle, adding 80g of water, starting stirring and heating to 70 ℃, slowly adding 11.2g of 30% liquid alkali, dissolving, and keeping pH=9-10; stirring for 20 minutes, adding 4g of active carbon, and carrying out suction filtration; 65-70 g of water is distilled out from the mother solution, the temperature is reduced to 5 ℃, then timing crystallization is started for 2 hours, and the temperature is controlled to be 0-5 ℃ in the crystallization process. Suction filtration, filter cake 60-70 ℃ blast drying 8 hours, get the finished product white solid 15.5g, yield 70.7%, HPLC purity 99.78% (remark: mother liquor can be used for next batch salification)
The obtained product is subjected to detection such as nuclear magnetic resonance hydrogen spectrum, carbon spectrum, mass spectrum and the like, and the results are shown in fig. 1-3:
Hydrogen spectrum: 1HNMR (d 6-DMSO): 11.75 (s, 1H, 4-position hydrogen atom), 8.66 (s, 1H, 1-position hydrogen atom), 7.56-7.54 (m, 2H, 5-position hydrogen atom), 6.66-6.65 (d, 2H, 6-position hydrogen atom), 6.43 (s, 1H, 6-position hydrogen atom), 6.06 (s, 2H, 7-position hydrogen atom)
Carbon spectrum: 13CNMR (d 6-DMSO), 160.38 (carbon atom at position 1), 157.46 (carbon atom at position 9), 153.34 (carbon atom at position 3), 128.92 (carbon atom at position 5), 124.11 (carbon atom at position 8),
112.70 (Carbon atom at 6-position), 98.27 (carbon atom at 2-position)
Mass spectrum TOF MS ES+ 262 (M+23)
TOF MS ES-:238(M-1)
The structural formula of the product is as follows:
example 2:
50g of vinylamine is put into a 5000ml reaction bottle, and stirring is started; adding 1700g of toluene and 700g of pyridine, and cooling; 338.5g of acetamido benzenesulfonyl chloride is added in batches below 25 ℃; after the material is fed, the temperature is kept at 27-32 ℃ and the reaction is stirred for 10 hours. After the completion of the reaction, 2100g of water was added thereto, followed by stirring for 30 minutes, whereby a large amount of white solid was precipitated. Suction filtration is carried out, and filter cakes are washed to PH=7; the filter cake was air-dried at 50-60℃for 8 hours to give 260g of intermediate I as a white solid in 93.2% yield.
1200G of absolute ethyl alcohol is put into a 5000ml reaction bottle, and stirring is started; 240g of intermediate I is added; heating to 40-45 ℃, and adding 24.0g of hydrobromic acid with 40 percent of content; adding 303g of NBS into the reaction kettle for 5 times, wherein the temperature is 40-45 ℃ when NBS is added each time, and the temperature is not more than 60 ℃ in the reaction process; after the NBS feeding is finished, controlling the temperature to be 50+/-5 ℃ for reacting for 0.5 hour;
77g of hydroxyurea is put into a reaction bottle, the temperature is raised to above 75 ℃ and after reflux appears, the timing reaction is started for 2 hours, and the like; after the reaction is finished, the temperature of the reaction solution is reduced to 10 ℃, then timing crystallization is started for 2 hours, and the temperature is controlled to be 10+/-5 ℃ in the crystallization process; suction filtration, rinsing with a small amount of ethanol, obtaining 250.3g of intermediate II white solid with 86.6 percent of yield
240G of intermediate II and 1356g of water are put into a 2000ml reaction bottle, and 444.0g of 30% liquid alkali and solution are added with stirring; heating to 70-75 ℃, preserving heat and stirring for 4 hours; after the reaction is finished, cooling to 45-55 ℃, and regulating the PH to 8-10 by using concentrated hydrochloric acid; adding 20g of active carbon, stirring for 20 minutes, and then carrying out suction filtration; the mother solution is cooled to below 30 ℃, then the pH value is regulated to be 4-5 by concentrated hydrochloric acid, a large amount of white solid is precipitated, and the mixture is stirred for 20 minutes and then is filtered. The filter cakes were rinsed 3 times with 1000ml of water, respectively. The filter cake was air-dried at 70-80℃for 8 hours to give 166.7g of an off-white solid. Purity 99.34% and molar yield 84.0%.
160G of sulfaisoxazole and 640g of water are added into a 2000ml reaction bottle, stirring is started, the temperature is raised to 70 ℃, 94.1g of 30% liquid alkali is slowly added, and the solution is clear, wherein the PH=9-10; stirring for 20 minutes, adding 16g of active carbon, and carrying out suction filtration; and (3) evaporating 500-600 g of water from the mother solution, cooling to 5 ℃, starting timing crystallization for 2 hours, and controlling the temperature to 0-5 ℃ in the crystallization process. Suction filtration, filter cake 60-70 ℃ blast drying 8 hours, get the finished product white solid 120.2g, yield 68.9%, HPLC purity 99.81% (remark: mother liquor can be used for next batch salification)
Example 3:
50g of vinylamine is put into a 5000ml reaction bottle, and stirring is started; adding 1700g of toluene and 700g of pyridine, and cooling; charging 369.3g of acetamido benzene sulfonyl chloride in batches below 25 ℃; after the material is fed, the temperature is kept at 27-32 ℃ and the reaction is stirred for 10 hours. After the completion of the reaction, 2100g of water was added thereto, followed by stirring for 30 minutes, whereby a large amount of white solid was precipitated. Suction filtration is carried out, and filter cakes are washed to PH=7; the filter cake was air-dried at 50-60℃for 8 hours to give 258g of intermediate I as a white solid in 92.5% yield.
1200G of absolute ethyl alcohol is put into a 5000ml reaction bottle, and stirring is started; 240g of intermediate I is added; heating to 40-45 ℃, and adding 36.0g of hydrobromic acid with 40 percent of content; 256.4g of NBS is added into the reaction kettle for 5 times, the temperature is 40-45 ℃ when NBS is added each time, and the temperature in the reaction process is not more than 60 ℃; after the NBS feeding is finished, controlling the temperature to be 50+/-5 ℃ for reacting for 0.5 hour;
80g of hydroxyurea is put into a reaction bottle, the temperature is raised to above 75 ℃ and after reflux appears, the timing reaction is started for 2 hours, and the like; after the reaction is finished, the temperature of the reaction solution is reduced to 10 ℃, then timing crystallization is started for 2 hours, and the temperature is controlled to be 10+/-5 ℃ in the crystallization process; suction filtering, eluting with a small amount of ethanol to obtain intermediate II white solid 247.1g with a yield of 85.5%
240G of intermediate II and 1356g of water are put into a 2000ml reaction bottle, and 444.0g of 30% liquid alkali and solution are added with stirring; heating to 70-75 ℃, preserving heat and stirring for 4 hours; after the reaction is finished, cooling to 45-55 ℃, and regulating the PH to 8-10 by using concentrated hydrochloric acid; adding 20g of active carbon, stirring for 20 minutes, and then carrying out suction filtration; the mother solution is cooled to below 30 ℃, then the pH value is regulated to be 4-5 by concentrated hydrochloric acid, a large amount of white solid is precipitated, and the mixture is stirred for 20 minutes and then is filtered. The filter cakes were rinsed 3 times with 1000ml of water, respectively. The filter cake was air-dried at 70-80℃for 8 hours to give 168.0g of an off-white solid. Purity 99.27% and molar yield 84.6%.
160G of sulfaisoxazole, 640g of water and mother liquor of the previous batch are added into a 2000ml reaction bottle, stirring is started, the temperature is raised to 70 ℃, 91.9g of 30% liquid alkali is slowly added, and the mixture is dissolved, wherein the PH=9-10; stirring for 20 minutes, adding 16g of active carbon, and carrying out suction filtration; and (3) evaporating 500-600 g of water from the mother solution, cooling to 5 ℃, starting timing crystallization for 2 hours, and controlling the temperature to 0-5 ℃ in the crystallization process. Suction filtration, filter cake 60-70 ℃ blast drying 8 hours, get the finished product white solid 166.1g, yield 95.1%, HPLC purity 99.68% (remark: mother liquor can be used for next batch salification)
Example 4:
50g of vinylamine is put into a 5000ml reaction bottle, and stirring is started; adding 1700g of toluene and 700g of pyridine, and cooling; charging 354.0g of acetamido benzene sulfonyl chloride in batches below 25 ℃; after the material is fed, the temperature is kept at 27-32 ℃ and the reaction is stirred for 10 hours. After the completion of the reaction, 2100g of water was added thereto, followed by stirring for 30 minutes, whereby a large amount of white solid was precipitated. Suction filtration is carried out, and filter cakes are washed to PH=7; the filter cake was air-dried at 50-60℃for 8 hours to give 263.2g of intermediate I as an off-white solid in 94.3% yield.
1200G of absolute ethyl alcohol is put into a 5000ml reaction bottle, and stirring is started; 240g of intermediate I is added; heating to 40-45 ℃, and adding 48.0g of hydrobromic acid with 40 percent of content; 256.4g of NBS is added into the reaction kettle for 5 times, the temperature is 40-45 ℃ when NBS is added each time, and the temperature in the reaction process is not more than 60 ℃; after the NBS feeding is finished, controlling the temperature to be 50+/-5 ℃ for reacting for 0.5 hour;
83.6g of hydroxyurea is put into a reaction bottle, the temperature is raised to above 75 ℃ and after reflux appears, the timing reaction is started for 2 hours, and the like; after the reaction is finished, the temperature of the reaction solution is reduced to 10 ℃, then timing crystallization is started for 2 hours, and the temperature is controlled to be 10+/-5 ℃ in the crystallization process; suction filtration, rinsing with a small amount of ethanol, obtaining 245.3g of intermediate II white solid with a yield of 84.9%
240G of intermediate II and 1356g of water are put into a 2000ml reaction bottle, and 444.0g of 30% liquid alkali and solution are added with stirring; heating to 70-75 ℃, preserving heat and stirring for 4 hours; after the reaction is finished, cooling to 45-55 ℃, and regulating the PH to 8-10 by using concentrated hydrochloric acid; adding 20g of active carbon, stirring for 20 minutes, and then carrying out suction filtration; the mother solution is cooled to below 30 ℃, then the pH value is regulated to be 4-5 by concentrated hydrochloric acid, a large amount of white solid is precipitated, and the mixture is stirred for 20 minutes and then is filtered. The filter cakes were rinsed 3 times with 1000ml of water, respectively. The filter cake was air-dried at 70-80℃for 8 hours to give 171.2.0g of an off-white solid. Purity 99.31%, molar yield 86.2%.
160G of sulfaisoxazole, 640g of water and mother liquor of the previous batch are added into a 2000ml reaction bottle, stirring is started, the temperature is raised to 70 ℃, 89.3g of 30% liquid alkali is slowly added, and the solution is clear, wherein the PH=9-10; stirring for 20 minutes, adding 16g of active carbon, and carrying out suction filtration; and (3) evaporating 500-600 g of water from the mother solution, cooling to 5 ℃, starting timing crystallization for 2 hours, and controlling the temperature to 0-5 ℃ in the crystallization process. Suction filtration, and blast drying of filter cake at 60-70 ℃ for 8 hours, thus obtaining 168.4g of white solid product with 96.9% yield and 99.62% purity by HPLC.
According to the examples 1-4, the final product sodium sulfaisoxazole obtained by the preparation and refining processes of the patent achieves higher purity, and the purity is more than 99.6%. In examples 2 to 4, the refining mother liquor is used mechanically, and the yield of the product can be obviously improved on the premise of ensuring the quality of the product.
The foregoing description is only of the preferred embodiments of the application and is not intended to limit the application.
Claims (8)
1. A preparation method of high-purity sodium sulfaisoxazole is characterized in that,
Step 1), adding vinylamine, toluene and pyridine into a reaction bottle; adding acetamido benzene sulfonyl chloride in batches under the temperature of 25 ℃; after the material is fed, stirring and reacting at the temperature of 27-32 ℃, adding water after the reaction is finished, stirring, filtering after a large amount of white solid is separated out, and washing a filter cake to be neutral; air drying the filter cake at 50-60deg.C to obtain intermediate I white solid；
Step 2), adding absolute ethyl alcohol and an intermediate I into a reaction bottle; heating to 40-45 ℃, and adding hydrobromic acid; controlling the temperature to be 40-45 ℃ and dividing NBS into batches in a reaction kettle, wherein the temperature in the reaction process is not more than 60 ℃; after NBS feeding is finished, controlling the temperature to be 50+/-5 ℃ for reaction;
Step 3) adding hydroxyurea into a reaction bottle, heating to above 75 ℃ and after reflux occurs, starting timing reaction, cooling the reaction liquid to 10 ℃ after the reaction is finished, starting timing crystallization, and controlling the temperature to 10+/-5 ℃ in the crystallization process; suction filtering, eluting with ethanol to obtain intermediate II white solid ；
Step 4), adding an intermediate II, water and liquid alkali into a reaction bottle, and dissolving; stirring at the temperature of 60-75 ℃, cooling to 45-55 ℃ after the reaction is finished, and regulating the PH to be 8-10 by using concentrated hydrochloric acid; cooling the mother solution to below 30 ℃, regulating the temperature to PH=4-5 by using concentrated hydrochloric acid, precipitating a large amount of white solids, and carrying out suction filtration; eluting a filter cake, and drying the filter cake at 70-80 ℃ by blowing for 8 hours to obtain white-like solid sulfaisoxazole;
step 5), adding sulfamethoxazole and water into a reaction bottle, heating to 65-75 ℃, adding liquid alkali, dissolving, and cleaning, wherein PH=9-10; stirring, adding active carbon, and suction filtering; evaporating part of water from the mother liquor, cooling to 0-10 ℃ and crystallizing; and (3) carrying out suction filtration, and carrying out blast drying on a filter cake at 60-70 ℃ to obtain a finished product of white solid sodium sulfaisoxazole, wherein mother liquor can replace a water jacket in the step for the next batch.
2. The method for preparing high-purity sodium sulfaisoxazole according to claim 1, wherein the molar ratio of vinylamine, toluene, pyridine and sulfacetamide chloride in the step 1) is: 1: 14-15: 6-7: 1.1-1.2; the weight ratio of vinylamine to water is: 1: 15-20.
3. The process for preparing high purity sodium sulfaisoxazole according to claim 1, wherein said step 2) intermediate i: hydrobromic acid: the molar ratio of NBS is: 1:0.1 to 0.2:1.1 to 1.3.
4. The process for preparing high purity sodium sulfaisoxazole according to claim 1, wherein step 3) intermediate i: the molar ratio of hydroxyurea is: 1:1 to 1.1.
5. The method for preparing high-purity sodium sulfaisoxazole according to claim 1, wherein the weight ratio of the liquid alkali to the intermediate II in the step 4) is: 7-8: 1.
6. The method for preparing high-purity sodium sulfaisoxazole according to claim 1, wherein the molar ratio of the sulfaisoxazole to the sodium hydroxide in the step 5) is: 1:1 to 1.05.
7. The method for preparing high-purity sodium sulfaisoxazole according to claim 1, wherein the liquid alkali in the step 5) is 30% liquid alkali.
8. The method for preparing high-purity sodium sulfaisoxazole according to claim 1, wherein the content of sodium sulfaisoxazole in the mother liquor in the step 5) is 40% -60%, and the crystallization temperature is 0-10 ℃.
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