CN113248439A - Synthesis method of pyrazole disulfide - Google Patents
Synthesis method of pyrazole disulfide Download PDFInfo
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- CN113248439A CN113248439A CN202110642388.5A CN202110642388A CN113248439A CN 113248439 A CN113248439 A CN 113248439A CN 202110642388 A CN202110642388 A CN 202110642388A CN 113248439 A CN113248439 A CN 113248439A
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- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 title claims abstract description 34
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 238000001308 synthesis method Methods 0.000 title description 3
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims abstract description 30
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000000243 solution Substances 0.000 claims abstract description 28
- PXJJSXABGXMUSU-UHFFFAOYSA-N disulfur dichloride Chemical compound ClSSCl PXJJSXABGXMUSU-UHFFFAOYSA-N 0.000 claims abstract description 26
- 125000003226 pyrazolyl group Chemical group 0.000 claims abstract description 22
- 238000006467 substitution reaction Methods 0.000 claims abstract description 18
- 238000001816 cooling Methods 0.000 claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- 239000000126 substance Substances 0.000 claims abstract description 14
- 238000010438 heat treatment Methods 0.000 claims abstract description 12
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 10
- 238000002156 mixing Methods 0.000 claims abstract description 10
- -1 pyrazole trithione Chemical compound 0.000 claims abstract description 9
- 239000012044 organic layer Substances 0.000 claims abstract description 7
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 6
- 238000001035 drying Methods 0.000 claims abstract description 6
- 238000006386 neutralization reaction Methods 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 239000007787 solid Substances 0.000 claims abstract description 5
- 239000011259 mixed solution Substances 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 17
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- 230000002194 synthesizing effect Effects 0.000 claims description 11
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- 235000010265 sodium sulphite Nutrition 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 239000012279 sodium borohydride Substances 0.000 claims description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 3
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 3
- 239000013078 crystal Substances 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 229910052717 sulfur Inorganic materials 0.000 abstract description 4
- 239000011593 sulfur Substances 0.000 abstract description 4
- 238000010189 synthetic method Methods 0.000 abstract description 3
- 239000000047 product Substances 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000012488 sample solution Substances 0.000 description 11
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 238000011084 recovery Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 239000012065 filter cake Substances 0.000 description 7
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- QPZYPAMYHBOUTC-UHFFFAOYSA-N 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]pyrazole-3-carbonitrile Chemical compound NC1=CC(C#N)=NN1C1=C(Cl)C=C(C(F)(F)F)C=C1Cl QPZYPAMYHBOUTC-UHFFFAOYSA-N 0.000 description 4
- 238000010812 external standard method Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 238000010606 normalization Methods 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 239000002351 wastewater Substances 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- HVQHXBNMBZJPLK-UHFFFAOYSA-N 1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-[(2-methylprop-2-en-1-yl)amino]-4-[(trifluoromethyl)sulfinyl]-1H-pyrazole-3-carbonitrile Chemical compound CC(=C)CNC1=C([S+]([O-])C(F)(F)F)C(C#N)=NN1C1=C(Cl)C=C(C(F)(F)F)C=C1Cl HVQHXBNMBZJPLK-UHFFFAOYSA-N 0.000 description 1
- WITMXBRCQWOZPX-UHFFFAOYSA-N 1-phenylpyrazole Chemical compound C1=CC=NN1C1=CC=CC=C1 WITMXBRCQWOZPX-UHFFFAOYSA-N 0.000 description 1
- ZOCSXAVNDGMNBV-UHFFFAOYSA-N 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[(trifluoromethyl)sulfinyl]-1H-pyrazole-3-carbonitrile Chemical compound NC1=C(S(=O)C(F)(F)F)C(C#N)=NN1C1=C(Cl)C=C(C(F)(F)F)C=C1Cl ZOCSXAVNDGMNBV-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- FNELVJVBIYMIMC-UHFFFAOYSA-N Ethiprole Chemical compound N1=C(C#N)C(S(=O)CC)=C(N)N1C1=C(Cl)C=C(C(F)(F)F)C=C1Cl FNELVJVBIYMIMC-UHFFFAOYSA-N 0.000 description 1
- 239000005899 Fipronil Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- XKMRRTOUMJRJIA-UHFFFAOYSA-N ammonia nh3 Chemical compound N.N XKMRRTOUMJRJIA-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012490 blank solution Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 229940013764 fipronil Drugs 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 238000001577 simple distillation Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/44—Oxygen and nitrogen or sulfur and nitrogen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a synthetic method of pyrazole disulfide, which comprises the following steps of 1) dissolving a pyrazole ring, and dissolving a pyrazole ring raw material in butyl acetate; adding a reducing agent weighed in advance into the solution, and fully dispersing and mixing; 2) dissolving sulfur chloride, namely dissolving the sulfur chloride in butyl acetate; 3) substitution reaction, namely mixing the solutions obtained in the step 1) and the step 2) and then carrying out substitution reaction; 4) performing neutralization reaction, namely adding an alkaline substance into the mixed solution obtained after the reaction in the step 3) to neutralize until the pH value is 6.5-7.5; 5) heating and layering, namely heating the reaction liquid neutralized in the step 4) to 80-100 ℃ until layering; 6) cooling and crystallizing, namely cooling and crystallizing the organic layer subjected to layering in the step 5); 7) and finally, drying to obtain a solid pyrazole disulfide product. The invention has the advantages that: the substitution reaction is milder, the generated impurities of the sulfur simple substance, the pyrazole trithione and the pyrazole tetrasulfide are reduced, the synthesis steps are few, and the production efficiency is high.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a synthetic method of pyrazole disulfide.
Background
5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethyl-phenyl) pyrazole disulfide, also known as 1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-cyano-5-amino-pyrazole-4-disulfide, is an important intermediate of N-phenylpyrazole pesticides such as fipronil, ethiprole and butene-fipronil.
The synthesis method in the prior art generally comprises the steps of dissolving 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethyl-phenyl) pyrazole in a chlorobenzene/acetonitrile mixed solvent, reacting with sulfur monochloride, neutralizing with ammonia water to a pH value of 6.5-7, and filtering to separate a filter cake containing a product disulfide. And washing the filter cake with a chlorobenzene and acetonitrile mixed solution, and drying to obtain the target product pyrazole disulfide. The industrial production is that 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethyl-phenyl) -1-H pyrazole reacts with sulfur monochloride, then ammonia water, ammonia gas or triethylamine are used for neutralization, filter pressing separation is carried out, filter cake is washed by hot water and dried to obtain pyrazole disulfide. In the process of synthesizing 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethyl-phenyl) pyrazole disulfide, solvents such as toluene, carbon tetrachloride, acetonitrile, chlorobenzene and the like are usually adopted, and when the solvents are used for synthesis, substitution reaction is severe, reaction temperature is difficult to control, sulfur chloride is easy to decompose to generate elemental sulfur, and pyrazole disulfide is easy to generate oxidation reaction to generate pyrazole trisulfide and pyrazole tetrasulfide in the presence of the elemental sulfur, so that the purity of products is influenced. Meanwhile, after the treatment by the process, the generated solvent contains a large amount of water, the separation is difficult (acetonitrile and water are subjected to azeotropy), and a large amount of wastewater is generated after the separation. The ammonia nitrogen and COD content in the wastewater is high, and the treatment is difficult.
Disclosure of Invention
The invention aims to solve the technical problems of reducing the generation of sulfur simple substance, pyrazole trithione and pyrazole tetrasulfide impurities in the substitution reaction process and improving the solvent recovery efficiency, and provides a synthetic method of pyrazole disulfide.
In order to achieve the purpose, the invention provides the following technical scheme: a method for synthesizing pyrazole disulfide comprises the following steps:
1) dissolving a pyrazole ring, namely dissolving a pyrazole ring raw material in butyl acetate; adding a reducing agent weighed in advance into the solution, and fully dispersing and mixing;
2) dissolving sulfur chloride, namely dissolving the sulfur chloride in butyl acetate;
3) substitution reaction, namely mixing the dissolving solutions obtained in the step 1) and the step 2) and then carrying out substitution reaction;
4) neutralization reaction, namely adding an alkaline substance into the mixed solution after the reaction in the step 3) for neutralization;
5) heating and layering, namely heating the reaction liquid neutralized in the step 4) to 80-100 ℃, and continuously heating until layering;
6) cooling and crystallizing, namely cooling and crystallizing the organic layer subjected to layering in the step 5);
7) and (3) drying, namely drying the solid obtained by filtering the crystal liquid in the step 6) to obtain a solid pyrazole disulfide product.
Further, the reducing agent in the step 1) is one of lithium aluminum hydride, sodium borohydride, potassium borohydride, sodium sulfite and sodium thiosulfate, and the addition amount of the reducing agent accounts for 0.01-0.1 of the molar weight of sulfur chloride.
Further, in the steps 1) and 2), the molar ratio of the sulfur chloride to the pyrazole ring is 1: 1.8-1: 2.0.
further, the temperature of the substitution reaction in the step 3) is 10-25 ℃.
Further, adding an alkaline substance in the step 4) to neutralize until the pH value is 6.5-7.5, wherein the alkaline substance is one or a mixture of sodium hydroxide solution, sodium carbonate solution, potassium carbonate solution and ammonia water.
Further, the solvent filtered in the cooling crystallization process in the step 6) can be used for repeated application.
Compared with the prior art, the invention has the beneficial effects that:
according to the method, sulfur chloride is diluted by butyl acetate and then mixed with a butyl acetate solution of the pyrazole ring, so that the substitution reaction temperature is controllable, the reaction is safer, the ratio of the sulfur chloride for the reaction is excessive, the production efficiency is improved, the loss caused by incomplete reaction of the raw materials of the pyrazole ring is avoided, and the generation of an impurity sulfur simple substance is reduced; the reducing agent with catalytic amount is added into the reaction system, so that impurities of the pyrazole trithione and the pyrazole tetrasulfide are reduced, and the product purity is high; in addition, by utilizing the characteristic that butyl acetate is only slightly soluble in water, most of water in the butyl acetate can be removed by simple layering during solvent recovery, and the solvent recovery treatment cost is greatly reduced; compared with the traditional method in the prior art, the method has the advantages that the whole steps are reduced, and the production efficiency is greatly improved.
Drawings
FIG. 1 is a scheme of the chemical synthesis of the present invention;
FIG. 2 is a schematic flow diagram of the process of the present invention;
FIG. 3 is a high performance liquid chromatogram of a pyrazole ring.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
The specific embodiment discloses a method for synthesizing pyrazole disulfide, which comprises the following steps: adding 150g (98.7 percent, 0.46mol) of pyrazole ring and 600g of butyl acetate into a dried 1000ml four-mouth bottle provided with a reflux condenser tube, simultaneously adding 0.95g (98.0 percent, 0.10mol) of sodium borohydride, fully stirring and mixing, and cooling to 10 ℃ for later use; 34g (98.0%, 0.25mol) of sulfur monochloride was mixed with 200g of butyl acetate and transferred to a 250mL constant pressure dropping funnel for use. And controlling the temperature, adding the sulfur chloride solution in the dropping funnel into the butyl acetate solution of the pyrazole ring within 30 minutes, raising the temperature to 23 ℃ after the dropwise addition is finished, and continuously stirring and reacting for 1 hour at the temperature to finish the substitution reaction. And (3) introducing air to blow off for 30 minutes under the vacuum condition, adding a 10% sodium carbonate solution, and adjusting the pH value to 7.0. Heating the neutralized reaction solution to 95 ℃ for layering; cooling the organic layer to below 10 ℃, preserving heat for 2 hours, carrying out suction filtration, distilling the filtrate to be used as a solvent to be continuously used in the next batch, and carrying out vacuum drying on the filter cake to obtain 165.3g of light yellow crystalline powder, wherein the purity of a target product is 99.84 percent and the content of the target product is 98.3 percent through high performance liquid chromatography detection, so that the yield is determined to be 93.5 percent. Specifically, the high performance liquid chromatography detection method adopts an area normalization method, and the content measurement is determined by adopting an external standard method. In other embodiments of the present invention, the reducing agent may also be lithium aluminum hydride, potassium borohydride, sodium sulfite or sodium thiosulfate. In other embodiments, the base used for neutralization may also be a mixture of one or more of sodium hydroxide solution, sodium carbonate solution, potassium carbonate solution, and ammonia water.
In the reaction process, the used butyl acetate is only slightly soluble in water, most of water in the butyl acetate can be removed by simple layering in the solvent recovery process, the filtration mother liquor only needs to separate out front fraction with high water content by a simple distillation process, the butyl acetate which is distilled out later and contains almost no water can be used for the synthesis of the next batch, and the solvent recovery treatment cost is greatly reduced.
Example 2
The specific embodiment discloses a method for synthesizing pyrazole disulfide, which comprises the following steps: adding 150g (98.7 percent, 0.46mol) of pyrazole ring and 600g of butyl acetate into a dried 1000ml four-mouth bottle provided with a reflux condenser tube, simultaneously adding 1.59g (98.0 percent, 0.05mol) of sodium sulfite, stirring and mixing to obtain a suspension, and cooling to 10 ℃ for later use; 34g (98.0%, 0.25mol) of sulfur monochloride was mixed with 200g of butyl acetate and transferred to a 250mL constant pressure dropping funnel for use. And controlling the temperature, adding the sulfur chloride solution in the dropping funnel into the butyl acetate solution of the pyrazole ring within 30 minutes, raising the temperature to 20 ℃ after the dropwise addition is finished, and continuously stirring and reacting for 1 hour at the temperature to finish the substitution reaction. And introducing air to blow off for 30 minutes under the vacuum condition, then dropwise adding a 10% sodium carbonate solution, and adjusting the pH value to 6.8. Heating the neutralized reaction liquid to 98 ℃ for layering; cooling the organic layer to below 10 ℃, preserving heat for 2 hours, carrying out suction filtration, distilling the filtrate to be used as a solvent to be continuously used in the next batch, and carrying out vacuum drying on the filter cake to obtain 164.4g of light yellow crystalline powder, wherein the purity of a target product is 99.82 percent, the content of the target product is 98.1 percent and the yield of the target product is 92.8 percent by high performance liquid chromatography. Specifically, the high performance liquid chromatography detection method adopts an area normalization method, and the content measurement is determined by adopting an external standard method.
Example 3
This example discloses the cyclic use of the filtered mother liquors of examples 1 and 2 for the synthesis of pyrazole disulfide.
The filtered mother liquor of the embodiments 1 and 2 is subjected to solvent recovery under the conditions of 70 ℃ and-0.09 MPa, and front fraction with higher water content is separated, so that butyl acetate with the water content less than or equal to 0.15 percent is obtained and used in the embodiment 3. Adding 150g (98.7 percent and 0.46mol) of pyrazole ring and 600g of butyl acetate (the water content is less than or equal to 0.15 percent) into a dried 1000ml four-mouth bottle provided with a reflux condenser pipe, simultaneously adding 1.59g (98.0 percent and 0.05mol) of sodium sulfite, stirring and mixing to obtain a suspension, and cooling to 10 ℃ for later use; 34g (98.0 percent and 0.25mol) of sulfur monochloride and 200g of butyl acetate (the water content is less than or equal to 0.15 percent) are mixed and transferred into a 250mL constant pressure dropping funnel for standby. And controlling the temperature, adding the sulfur chloride solution in the dropping funnel into the butyl acetate solution of the pyrazole ring within 35 minutes, raising the temperature to 18 ℃ after the dropwise addition is finished, and continuously stirring and reacting for 1 hour at the temperature to finish the substitution reaction. And introducing air to blow off for 30 minutes under the vacuum-pumping condition, then dropwise adding 20% ammonia water, and adjusting the pH value to 6.5. Heating the neutralized reaction liquid to 95 ℃ for layering; cooling the organic layer to below 10 ℃, preserving heat for 2 hours, carrying out suction filtration, distilling the filtrate to be used as a solvent to be continuously used in the next batch, and carrying out vacuum drying on the filter cake to obtain 165.5g of light yellow crystalline powder, wherein the purity of a target product is 99.85 percent, the content of the target product is 98.5 percent, and the yield of the target product is 93.8 percent. Specifically, the high performance liquid chromatography detection method adopts an area normalization method, and the content measurement is determined by adopting an external standard method.
Example 4
This embodiment discloses a method for synthesizing pyrazole disulfide, which comprises the following steps, different from embodiments 1 to 3, wherein the molar ratio of sulfur chloride to pyrazole ring in this embodiment is 1 to 2.
Adding 163g (98.7 percent, 0.5mol) of pyrazole ring and 600g of butyl acetate into a 1000ml four-mouth bottle provided with a reflux condenser pipe, simultaneously adding 0.95g (98.0 percent, 0.10mol) of sodium borohydride, fully stirring and mixing, and cooling to 10 ℃ for later use; 34g (98.0%, 0.25mol) of sulfur monochloride was mixed with 200g of butyl acetate and transferred to a 250mL constant pressure dropping funnel for use. And controlling the temperature, adding the sulfur chloride solution in the dropping funnel into the butyl acetate solution of the pyrazole ring within 30 minutes, raising the temperature to 23 ℃ after the dropwise addition is finished, and continuously stirring and reacting for 1 hour at the temperature to finish the substitution reaction. And (3) introducing air to blow off for 30 minutes under the vacuum condition, adding a 10% sodium carbonate solution, and adjusting the pH value to 7.0. Heating the neutralized reaction liquid to 95 ℃ for layering; cooling the organic layer to below 10 ℃, preserving heat for 2 hours, carrying out suction filtration, distilling the filtrate to be used as a solvent to be continuously used in the next batch, and carrying out vacuum drying on the filter cake to obtain 178.7g of light yellow crystalline powder, wherein the purity of a target product is 99.84 percent and the content of the target product is 98.5 percent through high performance liquid chromatography detection, so that the yield is determined to be 93.7 percent. Specifically, the high performance liquid chromatography detection method adopts an area normalization method, and the content measurement is determined by adopting an external standard method.
In addition, in the above examples, the conditions of hplc analysis of the obtained pyrazole disulfide product were:
high performance liquid chromatograph: agilent 1260/Shimadzu LC-20A; a chromatographic column: a 250mm by 4.6mm (i.d.) stainless steel column filled with a filler of ZORBAX SB-CN having a particle size of 5 μm. Mobile phase: acetonitrile + 0.16% phosphoric acid water ═ 55+ 45; flow rate: 1.0 mL/min; wavelength: 220 nm; sample introduction amount: 5 mu L of the solution; operating time: and (5) 50 min.
The specific operation steps are as follows:
standard sample solution: weighing 50.0mg of pyrazole disulfide standard substance, placing the pyrazole disulfide standard substance in a 50mL volumetric flask, adding 40mL of methanol for ultrasonic dissolution, returning to room temperature, diluting with methanol to a scale, and shaking up.
Sample solution: weighing 50.0mg of pyrazole disulfide sample, placing the pyrazole disulfide sample in a 50mL volumetric flask, adding 40mL of methanol for ultrasonic dissolution, returning to room temperature, diluting with methanol to a scale mark, and shaking up.
Under the operating conditions, after the instrument is stabilized, 1 needle of blank solution is fed, a plurality of needles of standard sample solution are continuously injected, and after the relative standard deviation RSD of the peak areas of the main peaks of the continuous 3 needles of the standard sample solution is not more than 2.0 percent, the standard sample solution, the sample solution and the standard sample solution are sequentially measured.
The content of 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethylphenyl) pyrazole was calculated according to the following formula:
wherein, in the formula:
Cu，Cs-the prepared concentrations (mg/mL) in the sample solution and the standard sample solution, respectively;
rs-a main peak response value corresponding to the standard sample solution;
ru-a main peak response value corresponding to the sample solution;
p-content of standard substance,%.
The single impurity content was calculated as follows:
100×Ai/A；
in the formula:
ai, A are respectively the peak area and the total peak area of other single impurities in the sample map.
According to the method, sulfur chloride is diluted by butyl acetate and then mixed with a butyl acetate solution of the pyrazole ring, so that the substitution reaction temperature is controllable, the reaction is safer, the ratio of the sulfur chloride for the reaction is excessive, the production efficiency is improved, and the loss caused by incomplete reaction of the raw materials of the pyrazole ring is avoided; by adding a catalytic amount of reducing agent into the reaction system, the impurities of the sulfur simple substance, the pyrazole trithione and the pyrazole tetrasulfide generated by the reaction are reduced, and the product purity is high; in addition, by utilizing the characteristic that butyl acetate is only slightly soluble in water, most of water in the butyl acetate can be removed by simple layering during solvent recovery, and the solvent recovery treatment cost is greatly reduced; compared with the traditional method in the prior art, the method has the advantages that the whole steps are reduced, and the production efficiency is greatly improved.
The embodiments of the present invention have been described in detail with reference to the accompanying drawings, but the present invention is not limited to the described embodiments. It will be apparent to those skilled in the art that various changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, and the scope of protection is still within the scope of the invention.
Claims (6)
1. The method for synthesizing the pyrazole disulfide is characterized by comprising the following steps of:
1) dissolving a pyrazole ring, namely dissolving a pyrazole ring raw material in butyl acetate; adding a reducing agent weighed in advance into the solution, and fully dispersing and mixing;
2) dissolving sulfur chloride, namely dissolving the sulfur chloride in butyl acetate;
3) substitution reaction, namely mixing the dissolving solutions obtained in the step 1) and the step 2) and then carrying out substitution reaction;
4) performing neutralization reaction, namely adding an alkaline substance into the mixed solution obtained after the reaction in the step 3) to neutralize until the pH value is 6.5-7.5;
5) heating and layering, namely heating the reaction liquid neutralized in the step 4) to 80-100 ℃, and continuously heating until layering;
6) cooling and crystallizing, namely cooling and crystallizing the organic layer subjected to layering in the step 5);
7) and (3) drying, namely drying the solid obtained by filtering the crystal liquid in the step 6) to obtain a solid pyrazole disulfide product.
2. The method for synthesizing pyrazole disulfide according to claim 1, wherein the reducing agent in step 1) is one of lithium aluminum hydride, sodium borohydride, potassium borohydride, sodium sulfite and sodium thiosulfate, and the addition amount of the reducing agent is 0.01-0.1 of the molar amount of sulfur chloride.
3. The method for synthesizing pyrazole disulfide according to claim 1, wherein the molar ratio of sulfur chloride to the pyrazole ring in steps 1) and 2) is 1:1.8 to 1: 2.0.
4. The method for synthesizing pyrazole disulfide according to claim 1, wherein the temperature of the substitution reaction in step 3) is 10-25 ℃.
5. The method for synthesizing pyrazole disulfide according to claim 1, wherein the step 4) is stopped by adding an alkaline substance to neutralize to a pH of 6.5-7.5, wherein the alkaline substance may be one or more of a sodium hydroxide solution, a sodium carbonate solution, a potassium carbonate solution and ammonia water.
6. The method for synthesizing pyrazole disulfide as claimed in claim 1, wherein the solvent filtered during the cooling crystallization in step 6) is used for repeated application.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US4513000A (en) * | 1981-10-29 | 1985-04-23 | Bayer Aktiengesellschaft | Insecticidal N-substituted O-pyrazol-4-yl carbamates and use thereof |
| JP2002249480A (en) * | 2001-02-22 | 2002-09-06 | Mitsubishi Chemicals Corp | Method of producing polyfluoroalkylsulfenyl compound |
| WO2023279671A1 (en) * | 2021-07-05 | 2023-01-12 | 浙江海正药业股份有限公司 | Method for synthesizing fipronil intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US4513000A (en) * | 1981-10-29 | 1985-04-23 | Bayer Aktiengesellschaft | Insecticidal N-substituted O-pyrazol-4-yl carbamates and use thereof |
| JP2002249480A (en) * | 2001-02-22 | 2002-09-06 | Mitsubishi Chemicals Corp | Method of producing polyfluoroalkylsulfenyl compound |
| WO2023279671A1 (en) * | 2021-07-05 | 2023-01-12 | 浙江海正药业股份有限公司 | Method for synthesizing fipronil intermediate |
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| CN113149909A (en) * | 2021-03-24 | 2021-07-23 | 台州达辰药业有限公司 | Preparation method of 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethyl-phenyl) pyrazole disulfide |
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