CN117447423A - Preparation method of thiadiazolyl sulfonyl chloride compounds and thiadiazolyl sulfonamide compounds - Google Patents
Preparation method of thiadiazolyl sulfonyl chloride compounds and thiadiazolyl sulfonamide compounds Download PDFInfo
- Publication number
- CN117447423A CN117447423A CN202311386763.XA CN202311386763A CN117447423A CN 117447423 A CN117447423 A CN 117447423A CN 202311386763 A CN202311386763 A CN 202311386763A CN 117447423 A CN117447423 A CN 117447423A
- Authority
- CN
- China
- Prior art keywords
- compound
- atoms
- formula
- preparation
- thiadiazole
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- -1 thiadiazolyl sulfonyl chloride compounds Chemical class 0.000 title claims abstract description 58
- 238000002360 preparation method Methods 0.000 title claims abstract description 38
- 229940124530 sulfonamide Drugs 0.000 title abstract description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 74
- 150000001875 compounds Chemical class 0.000 claims abstract description 54
- 238000000034 method Methods 0.000 claims abstract description 41
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims abstract description 37
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 33
- 238000002156 mixing Methods 0.000 claims abstract description 23
- 239000007864 aqueous solution Substances 0.000 claims abstract description 21
- 230000008569 process Effects 0.000 claims abstract description 20
- 239000000203 mixture Substances 0.000 claims abstract description 17
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims abstract description 16
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 16
- 238000010438 heat treatment Methods 0.000 claims abstract description 12
- 238000005576 amination reaction Methods 0.000 claims abstract description 11
- 125000004429 atom Chemical group 0.000 claims description 38
- 238000003756 stirring Methods 0.000 claims description 34
- 239000007787 solid Substances 0.000 claims description 29
- 238000001035 drying Methods 0.000 claims description 21
- 238000001914 filtration Methods 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 239000011259 mixed solution Substances 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 9
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 7
- 125000005067 haloformyl group Chemical group 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 150000002540 isothiocyanates Chemical class 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 229930194542 Keto Natural products 0.000 claims description 6
- 238000005660 chlorination reaction Methods 0.000 claims description 6
- 239000012065 filter cake Substances 0.000 claims description 6
- 125000000468 ketone group Chemical group 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 6
- 230000003647 oxidation Effects 0.000 claims description 6
- 238000007254 oxidation reaction Methods 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 5
- 229940001584 sodium metabisulfite Drugs 0.000 claims description 5
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 5
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000005917 3-methylpentyl group Chemical group 0.000 claims description 4
- 125000004920 4-methyl-2-pentyl group Chemical group CC(CC(C)*)C 0.000 claims description 4
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
- LBBIZPKEHXAXHI-UHFFFAOYSA-N isocyano thiocyanate Chemical compound [C-]#[N+]SC#N LBBIZPKEHXAXHI-UHFFFAOYSA-N 0.000 claims description 4
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 4
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 claims description 3
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 3
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 2
- 125000005518 carboxamido group Chemical group 0.000 claims description 2
- VINBVOMNIBDIPH-UHFFFAOYSA-N isocyanoimino(oxo)methane Chemical compound O=C=N[N+]#[C-] VINBVOMNIBDIPH-UHFFFAOYSA-N 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 59
- 230000007613 environmental effect Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- MEJAPGGFIJZHEJ-UHFFFAOYSA-N 5-acetamido-1,3,4-thiadiazole-2-sulfonyl chloride Chemical compound CC(=O)NC1=NN=C(S(Cl)(=O)=O)S1 MEJAPGGFIJZHEJ-UHFFFAOYSA-N 0.000 description 25
- BZKPWHYZMXOIDC-UHFFFAOYSA-N acetazolamide Chemical compound CC(=O)NC1=NN=C(S(N)(=O)=O)S1 BZKPWHYZMXOIDC-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 18
- 239000007791 liquid phase Substances 0.000 description 14
- DWSMAMSVZRCQMP-UHFFFAOYSA-N n-(2-sulfanylidene-3h-1,3,4-thiadiazol-5-yl)acetamide Chemical compound CC(=O)NC1=NN=C(S)S1 DWSMAMSVZRCQMP-UHFFFAOYSA-N 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- 238000002386 leaching Methods 0.000 description 9
- 238000005086 pumping Methods 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- 238000000967 suction filtration Methods 0.000 description 8
- 230000001276 controlling effect Effects 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 238000004321 preservation Methods 0.000 description 5
- GDGIVSREGUOIJZ-UHFFFAOYSA-N 5-amino-3h-1,3,4-thiadiazole-2-thione Chemical compound NC1=NN=C(S)S1 GDGIVSREGUOIJZ-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 239000012362 glacial acetic acid Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229960000571 acetazolamide Drugs 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 238000007112 amidation reaction Methods 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 239000012024 dehydrating agents Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000002360 explosive Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 150000004867 thiadiazoles Chemical class 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 102000003846 Carbonic anhydrases Human genes 0.000 description 1
- 108090000209 Carbonic anhydrases Proteins 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 238000004176 ammonification Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 210000001742 aqueous humor Anatomy 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000001886 ciliary effect Effects 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000004410 intraocular pressure Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000001261 isocyanato group Chemical group *N=C=O 0.000 description 1
- 125000002462 isocyano group Chemical group *[N+]#[C-] 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000010687 lubricating oil Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- 239000004317 sodium nitrate Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- LBLZPOGZQOBQKC-UHFFFAOYSA-N thiadiazole-4-sulfonamide Chemical class NS(=O)(=O)C1=CSN=N1 LBLZPOGZQOBQKC-UHFFFAOYSA-N 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
Classifications
-
- 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
-
- 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
- C07D285/135—Nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Abstract
The application relates to the technical field of organic synthesis, in particular to a thiadiazolyl sulfonyl chloride compound and a preparation method of a thiadiazolyl sulfonamide compound. The preparation method of the thiadiazolyl sulfonyl chloride compound comprises the following steps: mixing a compound of the formula (II), an aqueous solution of hydrochloric acid and acetonitrile at-20 to-10 ℃, adding N-chlorosuccinimide, mixing, heating the obtained mixture to 0 to 10 ℃ for performing a chlorooxidation reaction, and obtaining the compound of the formula (I); the preparation method of the thiadiazole sulfonamide compound comprises the following steps: and (3) carrying out amination reaction on the compound shown in the formula (I) and concentrated ammonia water to obtain the compound shown in the formula (III). The method can oxidize and halogenate the mercapto-substituted thiadiazole compound in one step to prepare the thiadiazole sulfonyl chloride compound, and has the advantages of high selectivity, simple process, safety, environmental protection and low cost.（Ⅱ）（Ⅰ）
Description
Technical Field
The application relates to the technical field of organic synthesis, in particular to a thiadiazolyl sulfonyl chloride compound and a preparation method of a thiadiazolyl sulfonamide compound.
Background
The thiadiazole sulfonyl chloride and the thiadiazole sulfonamide compound are widely applied to the fields of chemical industry, agriculture and medicine, and the thiadiazole derivatives have strong coordination capacity in terms of chemical structures, and hetero atoms can be used as polydentate ligands to form complexes with a plurality of metal ions, and sulfonyl is a common group for modifying the pharmaceutical activity; industrially, the compounds are commonly used as modification additives such as lubricating oil additives, resists, developers and the like; in addition, the compounds generally have antibacterial activity, such as 2-acetamido-1, 3, 4-thiadiazole-5-sulfonamide (acetazolamide) is used as an antibacterial pesticide, and the compounds also have carbonic anhydrase inhibitory activity and can reduce the generation of ciliary epithelial bicarbonate ions, thereby reducing the generation of aqueous humor by 50-60% and reducing intraocular pressure in glaucoma patients.
Therefore, the research on the preparation methods of the thiadiazolyl sulfonyl chloride and the thiadiazolyl sulfonamide compound is of great significance.
The current methods for preparing thiadiazolyl sulfonamide compounds include the following two classes: 1) The thiadiazole is reacted with a chlorosulfonating agent, 2) the mercapto-substituted thiadiazole is oxidized and further halogenated. Most chlorosulfonating agents have toxicity and strong irritation, have high requirements on production equipment, generate by-products such as sulfuric acid, hydrochloric acid and the like which are unfavorable for the environment, and are mainly based on the improvement and optimization of the method of the 2) in view of the increasingly serious environmental protection problem at present and the pursuit of green chemistry by people.
The method discloses a synthetic route of 2-acetamido-1, 3, 4-thiadiazole-5-sulfonamide, which is to introduce chlorine into 2-acetamido-5-mercapto-1, 3, 4-thiadiazole to perform a oxychlorination reaction to obtain 2-acetamido-5-chlorosulfonyl-1, 3, 4-thiadiazole. The chlorine used by the method has very strict operation requirements on factory equipment and workers, and once the chlorine leaks, serious consequences can be caused, so that the method has huge safe and environment-friendly working pressure on factories. Meanwhile, the reaction rate of the gas-liquid reaction is difficult to control, so that the consumption of chlorine gas participating in the reaction is difficult to control accurately, the incomplete reaction can be caused, partial reaction transition state impurities are generated, and the excessive chlorine gas can cause environmental pollution.
The method discloses a synthesis process for carrying out an oxidation chlorination reaction by using hydrogen peroxide and hydrochloric acid instead of chlorine, which avoids chlorine pollution, but the hydrogen peroxide is an explosive product, and has larger potential safety hazard in the storage and use processes of the hydrogen peroxide, so that the problems of safety and environmental protection cannot be thoroughly solved.
Based on the above, there is a need to develop a safer and more environment-friendly oxidation and chlorination method for preparing thiadiazolyl sulfonyl chloride compounds.
Disclosure of Invention
The purpose of the application is to provide a chlorooxidation method which can oxidize and halogenate sulfhydryl substituted thiadiazole compounds in one step to prepare thiadiazole sulfonyl chloride compounds. Compared with the traditional technology, the method has higher selectivity, has lower requirements on equipment and manpower, does not need to use toxic and explosive raw materials, is beneficial to environmental protection, has low equipment requirements, is simple to operate, safer in manual operation, is beneficial to saving production cost, can be produced on a large scale, and has industrial utilization value.
Still another object of the present invention is to provide a process for producing 2-acetamido-1, 3, 4-thiadiazole-5-sulfonamide (pure product) having a high purity by using a few intermediate steps, which can save production steps and reduce loss.
In one aspect of the present application, a method for preparing a thiadiazolyl sulfonyl chloride compound is provided, which includes the following steps:
mixing a compound of the formula (II), an aqueous solution of hydrochloric acid and acetonitrile at-20 to-10 ℃, adding N-chlorosuccinimide, mixing, heating the obtained mixture to 0 to 10 ℃ for oxidation chlorination reaction to obtain the compound of the formula (I),
（Ⅱ）/>（Ⅰ）；
wherein R is in the formula 1 Selected from: -H, -D, straight chain alkyl having 1 to 10C atoms, straight chain alkoxy having 1 to 10C atoms, branched chain alkyl having 3 to 10C atoms, cyclic alkyl having 3 to 10C atoms, branched chain alkoxy having 3 to 10C atoms, cyclic alkoxy having 3 to 10C atoms, keto having 1 to 10C atoms, alkoxycarbonyl having 2 to 10C atoms, aryloxycarbonyl having 7 to 10C atoms, carbamoyl, haloformyl, formyl, silyl, cyano, isocyano, thiocyanate, isothiocyanate, hydroxy, nitro, -CF 3 -Cl, -Br, -F, -I, or a suitable combination of the foregoing;
the aqueous solution of the hydrochloric acid contains 6-10% of hydrochloric acid by mass percent, and the weight ratio of the compound shown in the formula (II) to the aqueous solution of the hydrochloric acid is 1 (4-10);
the molar ratio of the compound of the formula (II) to the N-chlorosuccinimide is 1 (2-5).
In some embodiments, R 1 Selected from the group consisting of-H, -D, straight chain alkyl having 1 to 6C atoms, straight chain alkoxy having 1 to 6C atoms, branched alkyl having 3 to 6C atoms, cyclic alkyl having 3 to 6C atoms, branched alkoxy having 3 to 6C atoms, cyclic alkoxy having 3 to 6C atoms, keto having 1 to 6C atoms, andalkoxycarbonyl of 2 to 6C atoms, formyl, haloformyl, carboxamido, carbamoyl, silyl, cyano, isocyano, thiocyanate, isothiocyanate, hydroxy, nitro, -CF 3 -Cl, -Br, -F, -I, or a suitable combination of the foregoing.
In some embodiments, R 1 Selected from the group consisting ofOr->；
R 2 And R is 3 Each independently selected from: substituted or unsubstituted C 1 -C 6 Chain alkyl of C 3 -C 6 Cycloalkyl or C of (C) 1 -C 6 The substituted substituent is selected from-Cl, -Br, -F, -I, or a suitable combination of the foregoing.
In some embodiments, R 2 And R is 3 Each independently selected from the group consisting of substituted or unsubstituted: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, 2-ethylbutyl, 3-dimethylbutyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, cyclopentyl, 1-methylpentyl, 3-methylpentyl, 2-ethylpentyl, 4-methyl-2-pentyl, n-hexyl, 1-methylhexyl, 2-ethylhexyl, 2-butylhexyl, cyclohexyl, adamantyl.
In some embodiments, the weight to volume ratio of the compound of formula (ii) to the solvent is 1 g/(8-20) mL; and/or
In the step of adding N-chlorosuccinimide for mixing, the temperature of the mixed solution is controlled to be-10-0 ℃.
Compared with the traditional method, the preparation method of the thiadiazolyl sulfonyl chloride compound has better selectivity, reduces the generation of side reaction products, and has high purity of 97% -99% for example and 70% -85% for example. The thiadiazolyl sulfonyl chloride compound can be used as an intermediate for further ammonification reaction, so that the quality of the product thiadiazolyl sulfonamide is ensured.
In still another aspect of the present application, there is provided a method for preparing a thiadiazole sulfonamide compound, comprising the steps of:
providing the compound of formula (I) according to the preparation method of the thiadiazolyl sulfonyl chloride compound;
carrying out an amination reaction on the compound shown in the formula (I) and an ammonia water solution, adjusting the pH value to 3-4 after the amination reaction is finished to obtain a compound shown in the formula (III),
（Ⅲ）；
r in formula (III) 1 As defined above.
In some embodiments, the step of amination of the compound of formula (i) with an aqueous ammonia solution comprises:
and (3) adding the compound shown in the formula (I) into an ammonia water solution in batches at the temperature of minus 20 ℃ to minus 10 ℃ to mix, and reacting the obtained mixture at the temperature of minus 20 ℃ to minus 10 ℃ for 30min to 60min.
In some embodiments, the temperature of the mixture is maintained at-20℃to-10℃during the addition in portions, and/or
The mass percentage concentration of the ammonia water solution is 25% -28%, and the mass ratio of the compound of the formula (I) to the ammonia water solution is 1: (1-3).
In some embodiments, after the amination reaction is completed, the obtained mixed liquor is further subjected to post-treatment, and the step of post-treatment comprises the following steps:
adding aqueous solution of hydrochloric acid into the obtained mixed solution to adjust the pH to 3-4, and controlling the temperature of the mixed solution to be 0-20 ℃ in the adjusting process; then heating to 20-35 ℃, stirring for 1-2 h, and filtering to obtain a solid.
In some embodiments, in the step of post-treating, the solid obtained by filtration is further purified, the step of purifying comprising:
mixing the solid, water and active carbon, stirring at 100-110 ℃ for 1-2 h, hot filtering to obtain filtrate, adding sodium metabisulfite, mixing, and stirring at 100-110 ℃ for 0.5-1 h; cooling to 20-35 ℃, filtering to obtain a filter cake, washing the filter cake and drying.
The preparation method of the thiadiazole sulfonamide compound simplifies the process operation, has mild reaction temperature, is more environment-friendly, has low requirements on reaction equipment, has strong reaction operability, ensures the safety of production, and is a route suitable for industrial production.
Detailed Description
The present application is further illustrated below in conjunction with the embodiments and examples. It should be understood that these examples are illustrative only of the present application and are not intended to limit the scope of the present application. Furthermore, it is to be understood that various changes and modifications may be made by one skilled in the art after reading the teachings of this application, and such equivalents are intended to fall within the scope of the claims appended hereto.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein in the description of the application is for the purpose of describing particular embodiments only and is not intended to be limiting of the application.
Terminology
Unless otherwise indicated or contradicted, terms or phrases used herein have the following meanings:
"Cyclic alkyl" or "cycloalkyl" have the same meaning and are interchangeable.
"substituted" means that any one or more hydrogen atoms on a particular atom is substituted with a substituent, which may include deuterium and variants of hydrogen, provided that the valence of the particular atom is normal and the substituted compound is stable. The kind and number of substituents may be arbitrary on the basis that they can be chemically achieved. When the substituent is oxygen (i.e., =o), it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on the aromatic group.
"substituted or unsubstituted" means that the groups defined may or may not be substituted. When a defined group is substituted, it is understood that the defined group may be substituted with one or more defined substituents, which may be the same or different from each other when there are a plurality of substituents.
"alkyl" may mean straight, branched, and/or cyclic alkyl. The carbon number of the alkyl group may be 1 to 20, 1 to 10, or 1 to 6. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, 2-ethylbutyl, 3-dimethylbutyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, cyclopentyl, 1-methylpentyl, 3-methylpentyl, 2-ethylpentyl, 4-methyl-2-pentyl, n-hexyl, 1-methylhexyl, 2-ethylhexyl, 2-butylhexyl, cyclohexyl, adamantyl, and the like.
"halogen" or "halo" refers to F, cl, br or I.
"alkoxy" refers to a group of the structure "-O-alkyl", i.e., an alkyl group as defined above is attached to other groups via an oxygen atom. Phrases containing this term, suitable examples include, but are not limited to: methoxy (-O-CH) 3 or-OMe), ethoxy (-O-CH 2 CH 3 or-OEt) and t-butoxy (-O-C (CH) 3 ) 3 or-OtBu).
In the present application, carbonyl means-C (=o) -, carbamoyl means-C (=o) NH 2 Haloformyl means-C (=O) Z (wherein Z represents halogen), formyl means-C (=O) H, cyano means-CN, isocyano means-NC, isocyanato means-NCO, thiocyanate means-CNS, isothiocyanate means-NCS, hydroxy means-OH, amino means-NH 2 nitro-NO 2 Trifluoromethyl refers to-CF 3 。
In this application, "suitable combinations of the foregoing" refers to all suitable combinations of any two or more of the items listed above. For example, the radical R 0 Defined as selected from methyl, carbamoyl, or suitable combinations of the foregoing, can be understood as R 0 Is methyl (-CH) 3 ) Or carbamoyl (NH) 2 CO), or is methylcarbamoyl (CH 3 NH 2 CO-), or (NH) 2 COCH 2 -）。
The term "and/or," "and/or," as used herein, includes any one of two or more of the listed items in relation to each other, as well as any and all combinations of the listed items in relation to each other, including any two of the listed items in relation to each other, any more of the listed items in relation to each other, or all combinations of the listed items in relation to each other. It should be noted that, when at least three items are connected by at least two conjunctions selected from the group consisting of "and/or", "and/or", it should be understood that, in the present application, the technical solutions undoubtedly include technical solutions that are all connected by "logical and", and undoubtedly include technical solutions that are all connected by "logical or". For example, "a and/or B" includes three parallel schemes A, B and a+b. For another example, the technical schemes of "a, and/or B, and/or C, and/or D" include any one of A, B, C, D (i.e., the technical scheme of "logical or" connection), and also include any and all combinations of A, B, C, D, i.e., any two or three of A, B, C, D, and also include four combinations of A, B, C, D (i.e., the technical scheme of "logical and" connection).
Herein, "preferred", "better", etc. are merely embodiments or examples that describe better results, and it should be understood that they do not limit the scope of protection of the present application.
In this application, "further," "still further," "particularly," and the like are used for descriptive purposes and are not to be construed as limiting the scope of the present application.
In the present application, the technical features described in an open manner include a closed technical scheme composed of the listed features, and also include an open technical scheme including the listed features.
In this application, reference is made to a numerical interval (i.e., a numerical range), where the optional numerical distribution is considered continuous, and includes two numerical endpoints (i.e., a minimum value and a maximum value) of the numerical range, and each numerical value between the two numerical endpoints, unless otherwise indicated. When a numerical range merely points to integers within the numerical range, both end integers of the numerical range are included, as well as each integer between the two ends, unless expressly stated otherwise. Further, when a plurality of range description features or characteristics are provided, these ranges may be combined. In other words, unless otherwise indicated, the ranges disclosed herein are to be understood to include any and all subranges subsumed therein.
The temperature parameter in the present application is not particularly limited, and may be a constant temperature treatment or may vary within a predetermined temperature range. It should be appreciated that the constant temperature process described allows the temperature to fluctuate within the accuracy of the instrument control. Allows for fluctuations within a range such as + -0.5 deg.C, + -0.4 deg.C, + -0.3 deg.C, + -0.2 deg.C, + -0.1 deg.C.
In the present application, the weight may be a mass unit known in the chemical industry such as mu g, mg, g, kg.
Thermal filtration in this application refers to a filtration process that maintains the temperature of the solid-liquid mixture within a certain range using an instrument different from conventional filtration; preferably, the temperature of the thermal filtration is the reaction temperature, allowing for fluctuations within a range of + -5 ℃, + -4 ℃, + -3 ℃, + -2 ℃, + -1 ℃. For example, the reaction temperature is 110 ℃, and the temperature of the thermal filtration is selected from 105-115 ℃, 106-114 ℃, 107-113 ℃, 108-112 ℃, 109-111 ℃ and the like.
In one aspect, the application relates to a preparation method of thiadiazolyl sulfonyl chloride compounds, which has the advantages of simple preparation process, mild preparation conditions, one-step realization of oxidation and chlorination, high reaction efficiency, high yield and product purity, simple post-treatment and easy preparation.
In some embodiments, the method of preparing the thiadiazolyl sulfonyl chloride compound comprises the steps of:
mixing a compound of the formula (II), an aqueous solution of hydrochloric acid and acetonitrile at-20 to-10 ℃, adding N-chlorosuccinimide, mixing, heating the obtained mixture to 0 to 10 ℃ for oxidation chlorination reaction to obtain the compound of the formula (I),
（Ⅱ）/>（Ⅰ）；
wherein R is in the formula 1 Selected from: -H, -D, straight chain alkyl having 1 to 10C atoms, straight chain alkoxy having 1 to 10C atoms, branched chain alkyl having 3 to 10C atoms, cyclic alkyl having 3 to 10C atoms, branched chain alkoxy having 3 to 10C atoms, cyclic alkoxy having 3 to 10C atoms, keto having 1 to 10C atoms, alkoxycarbonyl having 2 to 10C atoms, aryloxycarbonyl having 7 to 10C atoms, carbamoyl, haloformyl, formyl, silyl, cyano, isocyano, thiocyanate, isothiocyanate, hydroxy, nitro, -CF 3 -Cl, -Br, -F, -I, or a suitable combination of the foregoing;
the aqueous solution of the hydrochloric acid contains 6-10% of hydrochloric acid by mass percent, and the weight ratio of the compound of the formula (II) to the aqueous solution of the hydrochloric acid is 1 (4-10);
the molar ratio of the compound of formula (II) to N-chlorosuccinimide is 1 (2-5).
The compounds of formula (II) may be obtained commercially or may be prepared from suitable starting materials by methods commonly employed in the art. In some embodiments, the compound of formula (ii) has the structure:。
in some embodiments, glacial acetic acid and 2-amino-5-mercapto-1, 3, 4-thiadiazole are amidated to produce a compound of formula (II).
Preferably, the molar ratio of glacial acetic acid to 2-amino-5-mercapto-1, 3, 4-thiadiazole is selected from (2-6): 1. examples are 2:1, 4:1, 6:1, etc.
Preferably, the amidation reaction temperature is 100 ℃ to 130 ℃.
Preferably, a dehydrating agent is also added during the amidation reaction to promote the forward progress of the reaction, such as acetic anhydride may be added.
Preferably, the molar ratio of the dehydrating agent to the 2-amino-5-mercapto-1, 3, 4-thiadiazole is selected from (1-2): 1. examples are 1:1, 1.2:1, 1.4:1, 2:1, etc.
In some embodiments, R 1 Selected from the group consisting of-H, -D, straight chain alkyl having 1 to 6C atoms, straight chain alkoxy having 1 to 6C atoms, branched chain alkyl having 3 to 6C atoms, cyclic alkyl having 3 to 6C atoms, branched chain alkoxy having 3 to 6C atoms, cyclic alkoxy having 3 to 6C atoms, keto having 1 to 6C atoms, alkoxycarbonyl having 2 to 6C atoms, carbamoyl, haloformyl, formyl, silyl, cyano, isocyano, isocyanate, thiocyanate, isothiocyanate, hydroxyl, nitro, -CF 3 -Cl, -Br, -F, -I, or a suitable combination of the foregoing.
In some embodiments, R 1 Selected from the group consisting ofOr->；
R 2 And R is 3 Each independently selected from: substituted or unsubstituted C 1 -C 6 Chain alkyl of C 3 -C 6 Cycloalkyl or C of (C) 1 -C 6 The substituted substituent is selected from-Cl, -Br, -F, -I, or a suitable combination of the foregoing.
In some embodiments, R 2 And R is 3 Each independently selected from the group consisting of substituted or unsubstituted: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, 2-ethylbutyl, 3-dimethylbutyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, cyclopentyl, 1-methylpentyl, 3-methylpentyl, 2-ethylpentyl, 4-methyl-2-pentyl, n-hexyl, 1-methylhexyl, 2-ethylhexyl, 2-butylhexylA group, a cyclohexyl group, an adamantyl group.
In some embodiments, R 1 Selected from: -H, -D, methyl, ethyl, methoxy, ethoxy,，，-CN，-NO 2 -Cl, -Br, -F or-I.
In some embodiments, the compound of formula (ii) has the structure:；
the structure of the compound of formula (I) is:。
alternatively, the weight ratio of the compound of formula (II) to acetonitrile is selected from 1 g/(8-20) mL, such as, for example, 1g/8mL, 1g/10mL, 1g/12mL, 1g/15mL, 1g/20mL, etc.;
the weight ratio of the compound of formula (II) to the aqueous solution of hydrochloric acid is 1:4-1:10, for example, 1:4, 1:4.14, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, etc., and the aqueous solution of hydrochloric acid contains 6% -10% of hydrochloric acid by mass percent, for example, 6%, 7%, 8%, 9%, 10% of hydrochloric acid, etc.
In some embodiments, the weight ratio of the compound of formula (II) to acetonitrile is 1 g/(8-20) mL, the mass percentage concentration of hydrochloric acid in the aqueous solution of hydrochloric acid is 6% -10%, and the weight ratio of the compound of formula (II) to the aqueous solution of hydrochloric acid is 1 (4-10).
In some embodiments, the compound of formula (II) is completely dissolved by stirring for 10min to 15min before adding the N-chlorosuccinimide and mixing.
In some embodiments, in the step of adding N-chlorosuccinimide for mixing, the temperature of the mixed solution is controlled to be-10-0 ℃.
In some embodiments, the N-chlorosuccinimide is added in portions in order to control the temperature of the mixture below 0 ℃, such as-10 ℃ to 0 ℃.
In some embodiments, the time of the chlorooxidation reaction is 0.5h to 2h.
In some embodiments, after the completion of the chlorooxidation reaction, the compound of formula (i) is obtained as an off-white solid by suction filtration, rinsing, and draining.
In still another aspect, the present application relates to a method for preparing thiadiazole sulfonamide compounds, which does not require toxic raw materials, has high yield of the product obtained in each step, simple post-treatment process, easy purification, and suitability for industrial production, and can be used for efficient preparation of acetazolamide.
In some embodiments, the method of preparing the thiadiazole sulfonamide compound comprises the steps of:
the preparation method of the thiadiazolyl sulfonyl chloride compound according to any one of the above technical schemes provides a compound of formula (I);
the compound of formula (I) and ammonia water are subject to amination reaction to prepare a compound of formula (III),
（Ⅲ）；
r in formula (III) 1 As defined above, no further description is provided herein.
In some embodiments, the compound of formula (III) has the structure。
In some embodiments, the step of amination of the compound of formula (i) with aqueous ammonia comprises:
adding the compound of the formula (I) into ammonia water in batches at the temperature of minus 20 ℃ to minus 10 ℃ for mixing, and reacting the obtained mixture at the temperature of minus 20 ℃ to minus 10 ℃ for 30min to 60min.
In some embodiments, the temperature of the mixture is maintained at-20℃to-10℃during the addition in portions.
In some embodiments, the mass percent concentration of the ammonia is 25% -28%, and the mass ratio of the compound of formula (i) to the ammonia is 1: (1-3);
optionally, the weight ratio of the compound of formula (I) to ammonia is 1:3 to 1:5, for example 1:3, 1:3.3, 1:4, 1:5, etc.
In some embodiments, after the amination reaction is completed, the resulting mixed liquor is further subjected to a post-treatment comprising the steps of:
adding aqueous solution of hydrochloric acid into the obtained mixed solution to adjust the pH to 3-4, and controlling the temperature of the mixed solution to be 0-20 ℃ in the adjusting process; then heating to 20-35 ℃, stirring for 1-2 h, and filtering to obtain a solid.
In some embodiments, in the step of adjusting the pH to 3-4, the hydrochloric acid aqueous solution used contains 5-7 mol/L hydrochloric acid; further, the amount of the aqueous solution of hydrochloric acid satisfies the following conditions: the weight ratio of the compound of formula (I) to the aqueous solution of hydrochloric acid is selected from 1:4 to 1:6, for example 1:4, 1:5, 1:6, etc.
In some embodiments, in the step of post-treatment, the solid obtained by filtration is further purified, the step of purifying comprising:
mixing solid, water and active carbon, stirring at 100-110 ℃ for 1-2 h, hot filtering to obtain filtrate, adding sodium metabisulfite, mixing, and stirring at 100-110 ℃ for 0.5-1 h; cooling to 20-35 ℃, filtering to obtain a filter cake, washing the filter cake and drying.
The following are some specific examples.
The experimental parameters not specified in the following specific examples are preferentially referred to the guidelines given in the application document, and may also be referred to the experimental manuals in the art or other experimental methods known in the art, or to the experimental conditions recommended by the manufacturer.
The starting materials and reagents referred to in the following specific examples may be obtained commercially or may be prepared by known means by those skilled in the art.
Example 1
(1) Preparation of 2-acetamido-5-mercapto-1, 3, 4-thiadiazole
Taking 57.1g of glacial acetic acid and 30g of 2-amino-5-mercapto-1, 3, 4-thiadiazole, mixing in a 250mL three-port reaction bottle, starting stirring, and heating to 115 ℃; 33g of acetic anhydride is dripped into a reaction bottle, the temperature is kept between 110 ℃ and 120 ℃ in the dripping process of the acetic anhydride, the temperature is kept at 115 ℃ for reaction for 1.5 hours after the dripping is completed, the temperature is reduced to 30 ℃ after the reaction is completed, the reaction bottle is subjected to suction filtration, leaching, pumping drying, and drying to obtain a pale yellow solid, namely 2-acetamido-5-mercapto-1, 3, 4-thiadiazole, and the pale yellow solid is weighed 37.98g, the liquid phase purity is 98.85%, and the molar yield of the 2-acetamido-5-mercapto-1, 3, 4-thiadiazole is 96.23%.
(2) Preparation of 2-acetamido-5-chlorosulfonyl-1, 3, 4-thiadiazole
Taking 41g of acetonitrile 100mL and 2mol/L hydrochloric acid solution in a 500mL three-port reaction bottle, starting stirring, and cooling to-10 ℃; 10g of 2-acetamido-5-mercapto-1, 3, 4-thiadiazole is added, the temperature is kept at minus 10 ℃ and stirred for 10min, 24.4g of N-chlorosuccinimide is added to a reaction bottle in batches, the temperature is controlled below 0 ℃ in the adding process, the temperature is kept at 0 ℃ to 10 ℃ for reaction for 0.5h, after the reaction is finished, suction filtration, leaching and pumping drying are carried out, thus obtaining off-white solid wet powder, namely 2-acetamido-5-chlorosulfonyl-1, 3, 4-thiadiazole, 16.88g is weighed, 11.35g is weighed after drying, the liquid phase purity is 97.73%, and the calculated molar yield of the 2-acetamido-5-chlorosulfonyl-1, 3, 4-thiadiazole is 82.32%.
(3) Preparation of 2-acetamido-1, 3, 4-thiadiazole-5-sulfonamide (crude)
Taking 33g of strong ammonia water in a 250mL three-port reaction bottle, starting stirring, cooling to-20 ℃, adding 10g of 2-acetamido-5-chlorosulfonyl-1, 3, 4-thiadiazole in batches, controlling the temperature between-20 ℃ and-10 ℃ in the adding process, carrying out heat preservation reaction for 0.5h, regulating the pH value of a reaction system to 3-4 by using 65.4g of 6mol/L hydrochloric acid after the reaction is completed, controlling the temperature below 20 ℃, heating to 30 ℃ after the acid regulation is completed, stirring for 1h, carrying out suction filtration, leaching, pumping, and drying to obtain an off-white solid, namely the 2-acetamido-1, 3, 4-thiadiazole-5-sulfonamide crude product. 6.63g of the mixture was weighed, the purity of the liquid phase was 97.13%, and the molar yield of the mixture was 72.15% based on 2-acetamido-1, 3, 4-thiadiazole-5-sulfonamide after drying.
(4) Preparation of 2-acetamido-1, 3, 4-thiadiazole-5-sulfonamide (pure product)
1000g of purified water and 20g of crude 2-acetamido-1, 3, 4-thiadiazole-5-sulfonamide are added into a 2000mL three-port reaction flask, stirring is started, and the temperature is raised to 100 ℃; adding 1g of active carbon, and stirring for 1h; filtering out active carbon by hot filtration, introducing filtrate into a reaction bottle, and heating to 100 ℃; adding 0.8g of sodium metabisulfite, and stirring for 0.5h under heat preservation; after the reaction is completed, the temperature is reduced to 20 ℃, the solution is filtered, leached and dried to obtain white solid which is 2-acetamido-1, 3, 4-thiadiazole-5-sulfonamide (pure product), 16.95g is weighed, and the liquid phase purity is 99.63%. After drying, the molar yield was 84.75% based on 2-acetamido-1, 3, 4-thiadiazole-5-sulfonamide (crude).
Example 2
The preparation of 2-acetamido-1, 3, 4-thiadiazole-5-sulfonamide (pure) was carried out in substantially the same manner as in example 1, except that 60g of hydrochloric acid solution was added in the step of preparing 2-acetamido-5-chlorosulfonyl-1, 3, 4-thiadiazole as an intermediate, and the prepared 2-acetamido-5-chlorosulfonyl-1, 3, 4-thiadiazole was as an off-white solid, 15.66g was weighed, 10.91g was weighed after drying, and the purity of the liquid phase was 97.93%, as calculated as 2-acetamido-5-chlorosulfonyl-1, 3, 4-thiadiazole molar yield was 79.16%.
Example 3
The preparation of 2-acetamido-1, 3, 4-thiadiazole-5-sulfonamide (pure) was carried out in substantially the same manner as in example 1, except that in the step of preparing 2-acetamido-5-chlorosulfonyl-1, 3, 4-thiadiazole as an intermediate, 100g of hydrochloric acid solution was added, and 2-acetamido-5-chlorosulfonyl-1, 3, 4-thiadiazole was prepared as an off-white solid, 15.32g was weighed, 10.60g was weighed after drying, and the purity of the liquid phase was 98.21%, as calculated as molar yield of 2-acetamido-5-chlorosulfonyl-1, 3, 4-thiadiazole was 76.86%.
Example 4
2-acetamido-1, 3, 4-thiadiazole-5-sulfonamide (pure product) was prepared by substantially the same preparation method as in example 1, except that in the step of preparing the intermediate 2-acetamido-5-chlorosulfonyl-1, 3, 4-thiadiazole, the temperature of the mixture was controlled to-10℃when N-chlorosuccinimide was added and mixed, the prepared 2-acetamido-5-chlorosulfonyl-1, 3, 4-thiadiazole was used as an off-white solid, 17.03g was weighed, 11.42g was weighed after drying, and the liquid phase purity was 98.08%, as a molar yield of 2-acetamido-5-chlorosulfonyl-1, 3, 4-thiadiazole was 82.81%.
Example 5
2-acetamido-1, 3, 4-thiadiazole-5-sulfonamide (pure product) was prepared in substantially the same manner as in example 1, except that in the step of preparing 2-acetamido-5-chlorosulfonyl-1, 3, 4-thiadiazole as an intermediate, N-chlorosuccinimide was added in an amount of five times the molar amount of 2-acetamido-5-mercapto-1, 3, 4-thiadiazole (10 g) as calculated, and the prepared 2-acetamido-5-chlorosulfonyl-1, 3, 4-thiadiazole was as an off-white solid, 16.88g was weighed, 11.42g was weighed after drying, and the liquid phase purity was 98.08%, as calculated, and the molar yield of 2-acetamido-5-chlorosulfonyl-1, 3, 4-thiadiazole was 82.81%.
Comparative example 1
Benzenesulfonyl chloride was prepared by a similar preparation method as in example 1, with the following steps:
mixing acetonitrile 80g and hydrochloric acid solution 26g with 2mol/L in a three-port 500mL reaction bottle, stirring, cooling to 10 ℃, adding N-chlorosuccinimide 20.4g, and mixing to obtain a mixed solution A. 6.3g of phenylmercaptan is dissolved in 30g of acetonitrile to prepare a mixed solution B, the mixed solution B is dropwise added into the mixed solution A, the temperature is controlled to be lower than 20 ℃ in the adding process, the temperature is kept at 10-20 ℃ for reaction for 30min after the dripping is finished, isopropyl ether (340 mL) is added into the system for diluting and stirring for 10min after the reaction is finished, the solution is separated, an organic layer is washed by NaCl aqueous solution (12 wt percent, 700 g) and the organic phase is concentrated in vacuo. 7.5g of a colorless liquid was obtained in the yield: 74.2%.
Comparative example 2
The preparation of 2-acetamido-5-chlorosulfonyl-1, 3, 4-thiadiazole using a completely different procedure from example 1 was performed as follows:
taking 74.2g of dichloromethane and 2g of sodium nitrate in a 250mL three-port reaction bottle, starting stirring, and cooling to 30 ℃; 2g of 2-acetamido-5-mercapto-1, 3, 4-thiadiazole is added, after stirring for 10min, 2.7g of trimethylchlorosilane is added to a reaction bottle in batches, stirring is carried out at 30 ℃ for 1.5h, after the reaction is completed, suction filtration, leaching and pumping are carried out, 1.1g of pale yellow solid wet powder is obtained, after drying, 0.75g is weighed, the liquid phase purity is 32.16%, and the yield is 27.1%.
Comparative example 3
The preparation of 2-acetamido-5-chlorosulfonyl-1, 3, 4-thiadiazole was carried out in essentially the same manner as in example 1, except that the partial reaction parameters were different, as follows:
150mL of acetonitrile and 61.5g of 2mol/L hydrochloric acid are taken in a 500mL three-port reaction bottle, stirring is started, and the temperature is raised to 50 ℃: 15.0g of 2-acetamido-5-mercapto-1, 3, 4-thiadiazole is added, stirring is carried out for 10min at the temperature of 50 ℃, 36.6g of N-chlorosuccinimide is added to a reaction bottle in batches, the temperature is controlled below 50 ℃ in the adding process, the reaction is carried out for 1h at the temperature of 50 ℃, after the reaction is completed, suction filtration, leaching and pumping drying are carried out, 3.15g of off-white solid wet powder is obtained, 2.79g of off-white solid wet powder is weighed after drying, the liquid phase purity is 14.56%, and the yield is 13.49%.
Comparative example 4
The preparation of 2-acetamido-1, 3, 4-thiadiazole-5-sulfonamide (pure) was carried out in substantially the same manner as in example 1, except that the crude product was prepared in a different manner as follows:
taking 100mL of acetonitrile and 41g of 2mol/L hydrochloric acid in a 500mL three-port reaction bottle, starting stirring, and cooling to-10 ℃: adding 10.0g of 2-acetamido-5-mercapto-1, 3, 4-thiadiazole, keeping the temperature at-10 ℃ and stirring for 10min, adding 24.4g of N-chlorosuccinimide into a reaction bottle in batches, controlling the temperature below 0 ℃ in the adding process, keeping the temperature at 0-10 ℃ and reacting for 0.5h, adjusting the pH to 4-5 by using 34g of 2mol/L sodium hydroxide solution after the reaction is finished, continuing to keep the temperature at 10 ℃ and stirring for 30min after the pH is adjusted, leaching, pumping, obtaining white-like solid wet powder, namely the 2-acetamido-5-chlorosulfonyl-1, 3, 4-thiadiazole, weighing 10.68g, weighing 7.20g after drying, and ensuring the liquid phase purity to be 96.45%, wherein the yield is 52.17%.
Comparative example 5
The preparation of 2-acetamido-5-chlorosulfonyl-1, 3, 4-thiadiazole was carried out in a completely different manner from example 1 and the preparation of pure product from crude product was carried out in substantially the same manner as in example 1, and the specific steps were as follows:
preparation of 2-acetamido-5-chlorosulfonyl-1, 3, 4-thiadiazole: 141g of glacial acetic acid and 215g of purified water are taken and added into a 500mL three-port reaction bottle, stirring is started, the temperature is reduced to below 0 ℃, then 30.0g of 2-acetamido-5-mercapto-1, 3, 4-thiadiazole is added, stirring is performed for 10min below 0 ℃ in a heat preservation mode, then chlorine gas is slowly introduced into the three-port reaction bottle, the internal temperature is not more than 10 ℃, the temperature is controlled below 10 ℃ in the adding process, the total chlorine gas flow is 60g, and after the chlorine gas addition is completed, the reaction system is changed from yellow turbid liquid to white turbid liquid. The temperature is kept between 0 ℃ and 10 ℃ for reaction for 0.5h, after the reaction is finished, suction filtration, leaching and pumping, 150g of ice water is used for leaching and pumping the solid wet powder, and the white-like solid wet powder is obtained, namely, 2-acetamido-5-chlorosulfonyl-1, 3, 4-thiadiazole, 40.3g is weighed, 31.6g is weighed after drying, the liquid phase purity is 95.12%, and the molar yield of the 2-acetamido-5-chlorosulfonyl-1, 3, 4-thiadiazole is 75.1%.
Preparation of 2-acetamido-1, 3, 4-thiadiazole-5-sulfonamide (crude): taking 99g of strong ammonia water in a 500mL three-port reaction bottle, starting stirring, cooling to-20 ℃, adding 30g of 2-acetamido-5-chlorosulfonyl-1, 3, 4-thiadiazole in batches, controlling the temperature between-20 ℃ and-10 ℃ in the adding process, carrying out heat preservation reaction for 0.5h, regulating the pH value of a reaction system to 3-4 by using 195.2g of 6mol/L hydrochloric acid after the reaction is completed, controlling the temperature below 20 ℃, heating to 30 ℃ after the acid regulation is completed, stirring for 1h, carrying out suction filtration, leaching, pumping, and drying to obtain an off-white solid, namely the 2-acetamido-1, 3, 4-thiadiazole-5-sulfonamide crude product. 20.5g of the mixture was weighed, the purity of the liquid phase was 92.16%, and the molar yield of the mixture was 74.3% based on 2-acetamido-1, 3, 4-thiadiazole-5-sulfonamide after drying.
Preparation of 2-acetamido-1, 3, 4-thiadiazole-5-sulfonamide (pure): 1000g of purified water and 20g of crude 2-acetamido-1, 3, 4-thiadiazole-5-sulfonamide are added into a 2000mL three-port reaction flask, stirring is started, and the temperature is raised to 100 ℃; adding 1g of active carbon, and stirring for 1h; filtering out active carbon by hot filtration, introducing filtrate into a reaction bottle, and heating to 100 ℃; adding 0.8g of sodium metabisulfite, and stirring for 0.5h under heat preservation; after the reaction is completed, the temperature is reduced to 20 ℃, the solution is filtered, leached and dried to obtain white solid, namely the 2-acetamido-1, 3, 4-thiadiazole-5-sulfonamide, 15.2g of the white solid is weighed, the liquid phase purity is 96.54%, and the molar yield of the 2-acetamido-1, 3, 4-thiadiazole-5-sulfonamide is 76.0% after the white solid is dried.
All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. Unless otherwise conflict with the purpose and/or technical solution of the present application, the present application relates to the cited documents which are incorporated by reference in their entirety for all purposes. When reference is made to a cited document in this application, the definitions of the relevant technical features, terms, nouns, phrases, etc. in the cited document are also incorporated by reference. Examples of the relevant technical features and preferred modes to be cited in the present application when the cited documents are referred to in the present application are incorporated by reference in the present application, but are not limited to being able to implement the present application. It should be understood that when a reference is made to the description herein, it is intended to control or adapt the present application in light of the description herein.
The technical features of the above-described embodiments and examples may be combined in any suitable manner, and for brevity of description, all of the possible combinations of the technical features of the above-described embodiments and examples are not described, however, as long as there is no contradiction between the combinations of the technical features, they should be considered to be within the scope described in the present specification.
The above examples merely represent a few embodiments of the present application and are not to be construed as limiting the scope of the claims. It should be noted that it would be apparent to those skilled in the art that various modifications and improvements could be made without departing from the spirit of the present application, which would be within the scope of the present application. Further, it will be understood that various changes or modifications may be made to the present application by those skilled in the art after reading the foregoing teachings, and equivalents thereof will be within the scope of the present application. It should also be understood that those skilled in the art, based on the technical solutions provided in the present application, can obtain technical solutions through logical analysis, reasoning or limited experiments, all fall within the protection scope of the claims attached to the present application. The scope of the patent is, therefore, indicated by the appended claims, and the description may be used to interpret the contents of the claims.
Claims (10)
1. The preparation method of the thiadiazolyl sulfonyl chloride compound is characterized by comprising the following steps of:
mixing a compound of the formula (II), an aqueous solution of hydrochloric acid and acetonitrile at-20 to-10 ℃, adding N-chlorosuccinimide, mixing, heating the obtained mixture to 0 to 10 ℃ for oxidation chlorination reaction to obtain the compound of the formula (I),
（Ⅱ）/>（Ⅰ）；
wherein R is in the formula 1 Selected from: -H, -D, straight chain alkyl having 1 to 10C atoms, straight chain alkoxy having 1 to 10C atoms, branched chain alkyl having 3 to 10C atoms, cyclic alkyl having 3 to 10C atoms, branched chain alkoxy having 3 to 10C atoms, cyclic alkoxy having 3 to 10C atoms, keto having 1 to 10C atoms, alkoxycarbonyl having 2 to 10C atoms, aryloxycarbonyl having 7 to 10C atoms, carbamoyl, haloformyl, formyl, silyl, cyano, isocyano, thiocyanate, isothiocyanate, hydroxy, nitro, -CF 3 -Cl, -Br, -F, -I, or a suitable combination of the foregoing;
the aqueous solution of the hydrochloric acid contains 6-10% of hydrochloric acid by mass percent, and the weight ratio of the compound shown in the formula (II) to the aqueous solution of the hydrochloric acid is 1 (4-10);
the molar ratio of the compound of the formula (II) to the N-chlorosuccinimide is 1 (2-5).
2. The process of claim 1, wherein R is 1 Selected from the group consisting of-H, -D, straight chain alkyl having 1 to 6C atoms, straight chain alkoxy having 1 to 6C atoms, branched chain alkyl having 3 to 6C atoms, cyclic alkyl having 3 to 6C atoms, branched chain alkoxy having 3 to 6C atoms, cyclic alkoxy having 3 to 6C atoms, keto having 1 to 6C atoms, alkoxycarbonyl having 2 to 6C atoms, formyl, haloformyl, carboxamido, carbamoyl, silyl, cyano, isocyano, isocyanate, thiocyanate, isothiocyanate, hydroxyl, nitro, -CF 3 -Cl, -Br, -F, -I, or a suitable combination of the foregoing.
3. The preparation method according to claim 2, wherein R 1 Selected from the group consisting ofOr->；
R 2 And R is 3 Each independently selected from: substituted or unsubstituted C 1 -C 6 Chain alkyl of C 3 -C 6 Cycloalkyl or C of (C) 1 -C 6 The substituted substituent is selected from-Cl, -Br, -F, -I, or a suitable combination of the foregoing.
4. The process according to claim 3, wherein R 2 And R is 3 Each independently selected from the group consisting of substituted or unsubstituted: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, 2-ethylbutyl, 3-dimethylbutyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, cyclopentyl, 1-methylpentyl, 3-methylpentyl, 2-ethylpentyl, 4-methyl-2-pentyl, n-hexyl, 1-methylhexyl, 2-ethylhexyl, 2-butylAnd (3) a hexyl group, a cyclohexyl group and an adamantyl group.
5. The preparation method according to any one of claims 1 to 4, wherein in the preparation step: the weight-volume ratio of the compound of the formula (II) to the solvent is 1 g/(8-20) mL; and/or
In the step of adding N-chlorosuccinimide for mixing, the temperature of the mixed solution is controlled to be-10-0 ℃.
6. The preparation method of the thiadiazole sulfonamide compound is characterized by comprising the following steps of:
the preparation method according to any one of claims 1 to 5, which provides the compound of formula (i);
the compound of formula (I) and ammonia water are subject to amination reaction to prepare a compound of formula (III),
（Ⅲ）；
r in formula (III) 1 As defined in any one of claims 1 to 5.
7. The process according to claim 6, wherein the step of subjecting the compound of formula (i) and an aqueous ammonia solution to an amination reaction comprises:
and (3) adding the compound shown in the formula (I) into ammonia water in batches at the temperature of minus 20 ℃ to minus 10 ℃ and mixing, and reacting the obtained mixture at the temperature of minus 20 ℃ to minus 10 ℃ for 30min to 60min.
8. The method according to claim 7, wherein the temperature of the mixture is maintained at-20 to-10 ℃ during the batch addition, and/or
The mass percentage concentration of the ammonia water is 25% -28%, and the mass ratio of the compound of the formula (I) to the ammonia water is 1: (1-3).
9. The method according to any one of claims 6 to 8, wherein after the amination reaction is completed, the obtained mixed solution is further subjected to post-treatment, and the post-treatment step includes:
adding aqueous solution of hydrochloric acid into the obtained mixed solution to adjust the pH to 3-4, and controlling the temperature of the mixed solution to be 0-20 ℃ in the adjusting process; then heating to 20-35 ℃, stirring for 1-2 h, and filtering to obtain a solid.
10. The method according to claim 9, wherein in the step of post-treatment, the solid obtained by filtration is further purified, the step of purifying comprising:
mixing the solid, water and active carbon, stirring at 100-110 ℃ for 1-2 h, hot filtering to obtain filtrate, adding sodium metabisulfite, mixing, and stirring at 100-110 ℃ for 0.5-1 h; cooling to 20-35 ℃, filtering to obtain a filter cake, washing the filter cake and drying.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311386763.XA CN117447423A (en) | 2023-10-24 | 2023-10-24 | Preparation method of thiadiazolyl sulfonyl chloride compounds and thiadiazolyl sulfonamide compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311386763.XA CN117447423A (en) | 2023-10-24 | 2023-10-24 | Preparation method of thiadiazolyl sulfonyl chloride compounds and thiadiazolyl sulfonamide compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117447423A true CN117447423A (en) | 2024-01-26 |
Family
ID=89592232
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311386763.XA Pending CN117447423A (en) | 2023-10-24 | 2023-10-24 | Preparation method of thiadiazolyl sulfonyl chloride compounds and thiadiazolyl sulfonamide compounds |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117447423A (en) |
-
2023
- 2023-10-24 CN CN202311386763.XA patent/CN117447423A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111393427A (en) | Synthetic method of sulfuryl pyraflufen | |
| CN105753731A (en) | Preparation method of 3-amino-4-methoxybenzaniline | |
| CN114805162A (en) | Continuous production method and device for meropenem side chain key intermediate O powder | |
| CN111574472B (en) | Synthesis method of 1, 2-benzisothiazolin-3-ketone compound | |
| CN117447423A (en) | Preparation method of thiadiazolyl sulfonyl chloride compounds and thiadiazolyl sulfonamide compounds | |
| AU2016380889B2 (en) | Process for preparing 1.1.3-Trioxo-1.2-benzothiazole-6-carboxamide | |
| CN105348184A (en) | Preparation method for sulfasalazine | |
| CN109535071B (en) | 2-amino-3-hydroxypyridine and preparation method and refining method thereof | |
| CN106632014A (en) | Preparation of 2-amino-5-chloropyridine | |
| JP3567135B2 (en) | Red reactive dye having monochlorotriazine group and acetoxyethyl sulfone group | |
| CN110105251A (en) | A kind of industrialized preparing process of ortho-nitrophenyl sulfonic acid chloride | |
| CN103044272B (en) | Preparation method of 4-nitroso-N-ethyl-N-hydroxyethyl aniline | |
| JP3789749B2 (en) | Method for producing thiosalicylic acid | |
| CN113999171A (en) | Synthesis method of high-content dipyrithione | |
| CN1050374C (en) | Temporary soluble blue dispersed dye and synthesis method thereof | |
| US4677209A (en) | Process for the preparation of 2-mercaptobenzoxazoles | |
| CN101575301A (en) | Preparation method of 2-amino-5-chlorobenzamide | |
| CN103910695B (en) | A kind of synthetic method of Febuxostat | |
| CN109574951A (en) | A kind of preparation method of Febuxostat | |
| CN111689881B (en) | Synthetic method of azosemide intermediate | |
| CA2289176C (en) | Producing z-isomer of acid salt of 2-aminothiazole derivative | |
| CN113248402B (en) | Method for preparing salicylonitrile by adopting micro-flow field technology | |
| JPH01149762A (en) | Production of 4-(alkylsulfonyl)-2-aminophenol | |
| CN101830831B (en) | Method for preparing ortho-diazanyl benzonitrile | |
| RU1773261C (en) | Method of arylsulfamides synthesis |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |