CN114478433A - Preparation method of 2-methyl-5-mercapto-1, 3, 4-thiadiazole dimer - Google Patents
Preparation method of 2-methyl-5-mercapto-1, 3, 4-thiadiazole dimer Download PDFInfo
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- CN114478433A CN114478433A CN202111488188.5A CN202111488188A CN114478433A CN 114478433 A CN114478433 A CN 114478433A CN 202111488188 A CN202111488188 A CN 202111488188A CN 114478433 A CN114478433 A CN 114478433A
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- FPVUWZFFEGYCGB-UHFFFAOYSA-N 5-methyl-3h-1,3,4-thiadiazole-2-thione Chemical class CC1=NN=C(S)S1 FPVUWZFFEGYCGB-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims abstract description 38
- KPULRXFDAIJSEP-UHFFFAOYSA-N 4-methylsulfanylthiadiazole Chemical class CSC1=CSN=N1 KPULRXFDAIJSEP-UHFFFAOYSA-N 0.000 claims abstract description 29
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims abstract description 29
- 239000013078 crystal Substances 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 24
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- 238000001816 cooling Methods 0.000 claims abstract description 11
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- 238000001035 drying Methods 0.000 claims abstract description 8
- 238000001914 filtration Methods 0.000 claims abstract description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 5
- 230000001590 oxidative effect Effects 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 3
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- 238000007254 oxidation reaction Methods 0.000 claims description 3
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- 239000000203 mixture Substances 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 39
- 238000011160 research Methods 0.000 abstract description 12
- 238000006243 chemical reaction Methods 0.000 abstract description 10
- 239000002994 raw material Substances 0.000 abstract description 8
- 229960001139 cefazolin Drugs 0.000 abstract description 5
- MLYYVTUWGNIJIB-BXKDBHETSA-N cefazolin Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 MLYYVTUWGNIJIB-BXKDBHETSA-N 0.000 abstract description 5
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- 229960003408 cefazolin sodium Drugs 0.000 description 10
- QPYXMRZUQWAHDP-UHFFFAOYSA-N 5-methylthiadiazole-4-thiol Chemical compound CC=1SN=NC=1S QPYXMRZUQWAHDP-UHFFFAOYSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000001228 spectrum Methods 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- HSHGZXNAXBPPDL-HZGVNTEJSA-N 7beta-aminocephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@@H]12 HSHGZXNAXBPPDL-HZGVNTEJSA-N 0.000 description 3
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 3
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- NVIAYEIXYQCDAN-CLZZGJSISA-N 7beta-aminodeacetoxycephalosporanic acid Chemical compound S1CC(C)=C(C(O)=O)N2C(=O)[C@@H](N)[C@@H]12 NVIAYEIXYQCDAN-CLZZGJSISA-N 0.000 description 2
- 238000005452 bending Methods 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
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- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 238000013341 scale-up Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 1
- DGYURGWZOSQCFG-GMSGAONNSA-N (6R,7R)-3-methyl-8-oxo-7-[[2-(tetrazol-1-yl)acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound CC1=C(N2[C@H](SC1)[C@H](NC(=O)Cn1cnnn1)C2=O)C(O)=O DGYURGWZOSQCFG-GMSGAONNSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- JUNAPQMUUHSYOV-UHFFFAOYSA-N 2-(2h-tetrazol-5-yl)acetic acid Chemical compound OC(=O)CC=1N=NNN=1 JUNAPQMUUHSYOV-UHFFFAOYSA-N 0.000 description 1
- DHHCHXFIEMGXCC-UHFFFAOYSA-N 2-methyl-3h-thiadiazole-5-thiol Chemical compound CN1NC=C(S)S1 DHHCHXFIEMGXCC-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
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- 239000001099 ammonium carbonate Substances 0.000 description 1
- 235000012501 ammonium carbonate Nutrition 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
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- 230000003115 biocidal effect Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
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- 208000019258 ear infection Diseases 0.000 description 1
- 206010014665 endocarditis Diseases 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
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- -1 peroxide hydrogen peroxide Chemical class 0.000 description 1
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- 208000013223 septicemia Diseases 0.000 description 1
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
- C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of a 2-methyl-5-mercapto-1, 3, 4-thiadiazole dimer, which is characterized by cooling an organic solvent to 10-15 ℃, adding 2-methyl-5-mercapto-1, 3, 4-thiadiazole, dissolving and clarifying, then dropwise adding a hydrogen peroxide or peracetic acid solution until crystal growth occurs, controlling the temperature, stirring and growing crystal, continuously dropwise adding a hydrogen peroxide solution or a peracetic acid solution, growing crystal, filtering and drying to constant weight. The method has the advantages of simple route, easily obtained product, conversion rate of generated methylmercaptothiadiazole dimer impurities of more than 97.5 percent, simple subsequent treatment steps, direct precipitation of the target product, no need of complex purification steps, high purity of the target product, maximum purity of 98.5 percent, residual raw material methylmercaptothiadiazole as single maximum impurity, and effective structure confirmation of other impurities of less than 0.2 percent. The invention fills the blank of the impurities in the research of the cefazolin impurities, and is beneficial to the subsequent structural analysis and pharmacological research of the impurities.
Description
Technical Field
The invention belongs to the field of chemical drug synthesis, and particularly relates to a preparation method of a 2-methyl-5-mercapto-1, 3, 4-thiadiazole dimer (methylmercaptothiadiazole dimer) in the quality research of cefazolin sodium.
Background
Ceftizolin Sodium (the common name in English is Cefazolin Sodium), which was originally developed by Nippon Tectoria, is the first generation of cephalosporin when being first marketed in Japan in 1971, has a wide antibacterial spectrum, is a leading antibiotic for treating gram-positive bacteria in international and domestic clinical medicine, is clinically applied to infections of respiratory tract, genitourinary system, skin soft tissue, bones, joints, biliary tract and the like caused by sensitive bacteria, can also be used for endocarditis, septicemia, pharynx and ear infections, and can also be used as a preventive medicine before surgical operations.
In the synthesis route of cefazolin sodium at home and abroad, 7-ACA is mostly adopted as a starting material, and the 3-position of the 7-ACA is modified by methylmercaptothiadiazole under the action of a catalyst to form a key intermediate TDA, however, in the synthesis process, the methylmercaptothiadiazole is influenced by high-temperature and high-humidity air conditions and is easy to generate a dimer compound, and the impurity is not recorded in pharmacopoeias of various countries at present and is a new synthesis process impurity in cefazolin sodium.
CN 110759932A discloses a method for synthesizing cefazolin impurity C by taking main impurity 7-ADCA in mother nucleus 7-ACA as raw material, the method firstly prepares anhydride of tetrazole acetic acid and then reacts with 7-ADCA to prepare; CN 110790775A discloses a method for synthesizing cefazolin impurity B by taking an azolin intermediate as a raw material, which is prepared by directly reacting the azolin intermediate with pivaloyl chloride used as a raw material in the cefazolin synthesizing process; CN 110759931A discloses a method for synthesizing cefazolin impurity K by taking cefazolin sodium as a raw material, which is prepared by reacting cefazolin sodium with ammonium carbonate; according to the three technical schemes, different impurities are prepared for research through a mother nucleus of a starting material, an intermediate and a finished product in the synthetic process of the cefazolin sodium, but the impurities possibly introduced by another key starting material 2-methyl-5-mercaptothiadiazole in the synthetic process of the cefazolin sodium are all considered.
At present, the national requirements for impurities in medicines are more strict, and particularly, the impurities in the medicines are required to be synthesized, structurally analyzed and subjected to pharmacological research, and impurity reference substances are adopted to carry out impurity research as far as possible. The content of the methylmercaptothiadiazole dimer generated in the synthesis process of the cefazolin sodium is low, so that the cefazolin sodium is inconvenient to separate; however, no synthetic preparation method for 2-methyl-5-mercapto-1, 3, 4-thiadiazole dimer impurities exists at present, and related research on the impurities is not facilitated.
Disclosure of Invention
Aiming at the defect that the synthesis and preparation method of 2-methyl-5-mercapto-1, 3, 4-thiadiazole dimer is unavailable at present, which causes the problem that the structure analysis and pharmacological research cannot be carried out, the invention provides the preparation method of the 2-methyl-5-mercapto-1, 3, 4-thiadiazole dimer, which has the advantages of simple route, easily obtained product and high purity.
The chemical reaction equation of the invention is as follows:
the preparation method of the 2-methyl-5-mercapto-1, 3, 4-thiadiazole dimer is characterized by comprising the following steps:
a. dissolving 2-methyl-5-mercapto-1, 3, 4-thiadiazole: cooling an organic solvent to 10-15 ℃, adding 2-methyl-5-mercapto-1, 3, 4-thiadiazole, dissolving and clarifying, wherein the mass concentration of the 2-methyl-5-mercapto-1, 3, 4-thiadiazole in the organic solvent is 10% -20%, and the organic solvent is N, N-dimethylformamide, N-dimethylacetamide or dimethyl sulfoxide;
b. oxidation reaction of 2-methyl-5-mercapto-1, 3, 4-thiadiazole with an oxidant: dissolving and clarifying 2-methyl-5-mercapto-1, 3, 4-thiadiazole, then dropwise adding a hydrogen peroxide solution or a peroxyacetic acid solution until crystal growth occurs, controlling the temperature to be 30-35 ℃, stirring and growing the crystal for 30min, then continuously dropwise adding the hydrogen peroxide solution or the peroxyacetic acid solution, and growing the crystal for 30min at the temperature of 30-35 ℃;
c. growing crystal, filtering and drying: and (3) cooling the crystallization liquid to 5-10 ℃, growing crystals for 30min, filtering, and drying at-0.08 to-0.10 Mpa and 50-80 ℃ to constant weight to obtain the target product.
The mass concentration of the hydrogen peroxide solution is 30%, and the mass concentration of the peroxyacetic acid is 20%.
The mass concentration of the hydrogen peroxide solution is 30%.
The molar ratio of the hydrogen peroxide or the peroxyacetic acid to the methyl mercaptothiadiazole is 2.0-4.5: 1.
The molar ratio of the hydrogen peroxide or the peroxyacetic acid to the methyl mercapto thiadiazole is 3: 1.
The mass concentration of the 2-methyl-5-mercapto-1, 3, 4-thiadiazole in the organic solvent is 15%.
And dropwise adding a hydrogen peroxide solution or a peracetic acid solution until crystal growth is realized, and stirring and crystal growth is carried out for 30min at the temperature of 30-35 ℃.
The invention achieves the technical progress that:
(1) according to the invention, the methyl mercapto thiadiazole is taken as a raw material, a common solvent N, N-dimethylformamide, N-dimethylacetamide or dimethyl sulfoxide is taken as a reaction system, and a target product, namely methyl mercapto thiadiazole dimer impurity, is generated by oxidation of common peroxide hydrogen peroxide and peracetic acid.
(2) The invention discovers that the conversion rate of converting the methyl mercapto thiadiazole into the methyl mercapto thiadiazole dimer is very low, and is only 30-40% under the condition of oxidizing the dimethyl sulfoxide or iodine weak oxidant.
(3) The invention controls the mass concentration of raw material methylmercaptothiadiazole in N, N-dimethylformamide, N-dimethylacetamide or dimethyl sulfoxide to be 10-20%, and the reaction molar ratio of the methylmercaptothiadiazole to hydrogen peroxide and peroxyacetic acid is 1: 2.0-4.5, and generating the methyl mercapto thiadiazole dimer impurity under the stirring reaction condition of 30-35 ℃, wherein the conversion rate can reach more than 97.5%.
(4) The method has the advantages of simple subsequent treatment steps, high reaction conversion rate and less side reactions, the reaction system can be directly used as a crystallization system, the subsequent purification step is not needed, the target product is directly separated out, the complex purification step is not needed, the purity of the target product is high, the maximum purity is 98.5%, the single maximum impurity is the residual raw material methyl mercapto thiadiazole, and other impurities are less than 0.2%, so that the method can be used for effective structure confirmation and can be used as an impurity reference substance.
(5) The synthetic route for preparing the target product is novel, the synthesized target product is a new synthetic impurity, the blank of the impurity in the foreign matter research of cefazolin at home and abroad is filled, and the subsequent structural analysis and pharmacological research of the impurity are facilitated.
Drawings
FIG. 1 is an infrared spectrum of methylmercaptothiadiazole dimer impurity of the present invention.
FIG. 2 is a MS spectrum of the methylmercaptothiadiazole dimer impurity of the present invention.
FIG. 3 shows the methylmercaptothiadiazole dimer impurity of the present invention1H-NMR spectrum.
FIG. 4 shows the methylmercaptothiadiazole dimer impurity of the present invention13C-NMR spectrum.
Detailed Description
Example 1:
adding 420g of N, N-dimethylformamide into a 1000ml clean four-mouth bottle, starting stirring, cooling to 15 ℃, adding 100.0g of methylmercaptothiadiazole, stirring to dissolve, dropwise adding 310ml of 30% hydrogen peroxide solution, controlling the process temperature to be not more than 35 ℃, stopping dropwise adding the hydrogen peroxide solution after crystal precipitation is observed, controlling the temperature to be 30-35 ℃, stirring and growing crystals for 30min, then continuously dropwise adding the residual hydrogen peroxide solution, controlling the temperature to be 30-35 ℃, stirring and reacting for 30min, cooling to 5 ℃, growing crystals for 30min, filtering, drying a filter cake under reduced pressure for 3h at 60 ℃ by using an oven until the weight is constant to obtain 59.5g of a target product, and detecting that the purity (HPLC) of the methylmercaptothiadiazole dimer of the target product is 97.9%. MS and NMR detection prove that the target product prepared in the embodiment has the structure of the methylmercaptothiadiazole dimer impurity, MS, and,1H-NMR、13The detection spectra of C-NMR are shown in FIGS. 1 to 3.
Structure analysis:
1. as can be seen from the infrared spectrum of the methylmercaptothiadiazole dimer impurity in FIG. 1, the absorption peak near 2741.5cm-1 is C-H stretching vibration on methyl, the absorption peak near 1388.4 cm-1 is C-H bending vibration on methyl, and the absorption peaks near 1045.5 and 982.2 cm-1 are methyl swinging vibration, which indicates that methyl exists in the molecule; the absorption peaks near 1487.2 and 1420.1 cm < -1 > are C-N stretching vibration, which shows that the molecule contains CN bonds; the absorption peaks near 1209.5 and 1187.2 cm-1 were C-C stretching vibrations, the absorption peak near 1082.8 cm-1 was N-C-S stretching vibrations, the absorption peak near 766.0 cm-1 was thiazole ring bending vibrations, and the absorption peaks at 644.8 and 603.8 cm-1 were C-S stretching vibrations of carbonyl groups, indicating that the molecules contained thiazole rings.
531.1 and 494.4 cm < -1 > of weak absorption peak positions of S-S bond stretching vibration absorption peaks, the S-S bond exists in molecules, and an infrared absorption spectrum shows that the sample molecules contain characteristic functional groups such as alkyl, thiazole rings, S-S bonds and the like.
2. From the MS spectrum of the methylmercaptothiadiazole dimer impurity in FIG. 2, it can be seen that under the positive ion mode, the impurity is in the form ofm/zIon peaks at 262.9552, 284.9368, and 300.9114 correspond to [ M + H ], respectively]+、[M+Na]+And [ M + K]+(ii) a The above test results are consistent with the molecular weight of the methylmercaptothiadiazole dimer.
3. From FIG. 3 of methylmercaptothiadiazole dimer impurities1H-NMR spectrum shows that 1 group of proton signals appear in the sample, and the total content of 6 protons delta in the sample molecule is known according to the integral area ratioH2.785 (s, 6H) to methyl H-1&H-1', the analysis result is consistent with the molecular structure of the methylmercaptothiadiazole dimer.
4. From FIG. 4 of methylmercaptothiadiazole dimer impurities13The C-NMR spectrum shows that the sample contains a carbon signal, delta, of 3 groups of 6 carbons in totalC168.872 belong to C-3&C-3',δC165.958 belong to C-2&C-2',δC16.009 belongs to methyl C-1&C-1', the analysis result is consistent with the molecular structure of the methylmercaptothiadiazole dimer.
In summary, NMR spectra of methylmercaptothiadiazole dimer (A), (B), (C1H-NMR) andcarbon spectrum (C)13C-NMR) confirmed C, H assignment to be consistent with the sample molecular structural formula. The infrared and mass spectrum results of the sample are consistent with the structure, and the correctness of the structure is verified.
In summary, the target product sample has the structural formula:
example 2:
adding 150g of N, N-dimethylacetamide into a 500ml clean four-mouth bottle, starting stirring, cooling to 13 ℃, adding 26.5g of methylmercaptothiadiazole, stirring to dissolve, dropwise adding 155ml of peroxyacetic acid solution with the mass concentration of 20%, controlling the process temperature to be not more than 35 ℃, stopping dropwise adding the peroxyacetic acid solution after crystal precipitation is observed, controlling the temperature to be 30-35 ℃, stirring and growing crystals for 35min, then continuously dropwise adding the rest peroxyacetic acid solution, controlling the temperature to be 30-35 ℃, stirring and reacting for 30min, cooling to 9 ℃, growing crystals for 30min, filtering, drying a filter cake in an oven at 50 ℃ under reduced pressure for 3h until the weight is constant, obtaining 16.9g of a target product, and detecting that the purity (HPLC) of the target product methylmercaptothiadiazole dimer in the embodiment is 98.4%.
Example 3:
adding 180g of dimethyl sulfoxide into a 500ml clean four-mouth bottle, starting stirring, cooling to 10 ℃, adding 22.0g of methylmercaptothiadiazole, stirring to dissolve, dropwise adding 50ml of hydrogen peroxide solution with the mass concentration of 30%, controlling the process temperature to be not more than 35 ℃, stopping dropwise adding the hydrogen peroxide solution after crystal precipitation is observed, controlling the temperature to be 30-35 ℃, stirring and growing crystals for 30min, then continuously dropwise adding the residual hydrogen peroxide solution, controlling the temperature to be 30-35 ℃, stirring and reacting for 30min, cooling to 7 ℃, growing crystals for 30min, filtering, drying a filter cake under reduced pressure for 3h at 70 ℃ by using an oven until the weight is constant, obtaining 12.4g of a target product, and detecting that the purity (HPLC) of the target product methylmercaptothiadiazole dimer in the embodiment is 98.5%.
At present, the technical scheme of the invention has been subjected to laboratory scale-up pilot test, namely a small-scale test of products before large-scale mass production, and the reproducibility of the process scale-up process is good; after the pilot plant test is finished, user use investigation is conducted in a small range, and the investigation result shows that the impurity use user satisfaction degree is high, the impurity use user satisfaction degree can be used as an impurity reference substance, and related toxicological research work is conducted. The technical scheme of the invention is to design a reaction route and develop reaction conditions on the basis of independent research, prepare a target compound, analyze and confirm the structure, and report no literature or data at home and abroad on the synthesis process of the compound.
Claims (7)
1. A preparation method of 2-methyl-5-mercapto-1, 3, 4-thiadiazole dimer is characterized by comprising the following steps:
a. dissolving 2-methyl-5-mercapto-1, 3, 4-thiadiazole: cooling an organic solvent to 10-15 ℃, adding 2-methyl-5-mercapto-1, 3, 4-thiadiazole, dissolving and clarifying, wherein the mass concentration of the 2-methyl-5-mercapto-1, 3, 4-thiadiazole in the organic solvent is 10% -20%, and the organic solvent is N, N-dimethylformamide, N-dimethylacetamide or dimethyl sulfoxide;
b. oxidation reaction of 2-methyl-5-mercapto-1, 3, 4-thiadiazole with an oxidant: dissolving and clarifying 2-methyl-5-mercapto-1, 3, 4-thiadiazole, then dropwise adding a hydrogen peroxide solution or a peroxyacetic acid solution until crystal growth is achieved, controlling the temperature to be 30-35 ℃, stirring and growing the crystal for 30-35 min, then continuously dropwise adding the hydrogen peroxide solution or the peroxyacetic acid solution, and growing the crystal for 30min at the temperature of 30-35 ℃;
c. growing crystal, filtering and drying: and (3) cooling the crystallization liquid to 5-10 ℃, growing crystals for 30min, filtering, and drying at-0.08 to-0.10 Mpa and 50-80 ℃ to constant weight to obtain the target product.
2. The method according to claim 1, wherein the concentration of the peroxyacetic acid is 20% by mass.
3. The method according to claim 1, wherein the hydrogen peroxide solution has a concentration of 30% by mass.
4. The method for preparing 2-methyl-5-mercapto-1, 3, 4-thiadiazole dimer according to claim 1, wherein the molar ratio of hydrogen peroxide or peracetic acid to methylmercaptothiadiazole is 2.0-4.5: 1.
5. The method of claim 1, wherein the molar ratio of hydrogen peroxide or peroxyacetic acid to methylmercaptothiadiazole is 3: 1.
6. The method according to claim 1, wherein the mass concentration of 2-methyl-5-mercapto-1, 3, 4-thiadiazole in the organic solvent is 15%.
7. The preparation method of the 2-methyl-5-mercapto-1, 3, 4-thiadiazole dimer according to claim 1, wherein a hydrogen peroxide solution or a peracetic acid solution is added dropwise until crystal growth occurs, and the temperature is controlled at 30-35 ℃ and the mixture is stirred for crystal growth for 30 min.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US20090151779A1 (en) * | 2006-03-29 | 2009-06-18 | Amer Hammami | Redox Couples, Compositions and Uses Thereof |
| CN103597023A (en) * | 2011-04-14 | 2014-02-19 | 米其林企业总公司 | Rubber composition comprising a thiadiazole derivative |
| CN110590814A (en) * | 2019-09-29 | 2019-12-20 | 天津力生制药股份有限公司 | Synthetic method of dimer impurity generated in production of cefazolin sodium |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090151779A1 (en) * | 2006-03-29 | 2009-06-18 | Amer Hammami | Redox Couples, Compositions and Uses Thereof |
| CN103597023A (en) * | 2011-04-14 | 2014-02-19 | 米其林企业总公司 | Rubber composition comprising a thiadiazole derivative |
| CN110590814A (en) * | 2019-09-29 | 2019-12-20 | 天津力生制药股份有限公司 | Synthetic method of dimer impurity generated in production of cefazolin sodium |
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