CN111233783B - Synthetic method of isothiazol-4-yl disulfide derivative - Google Patents
Synthetic method of isothiazol-4-yl disulfide derivative Download PDFInfo
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- XPJHVZWZBFWOLZ-UHFFFAOYSA-N 4-(1,2-thiazol-4-yldisulfanyl)-1,2-thiazole Chemical class S1N=CC(=C1)SSC=1C=NSC=1 XPJHVZWZBFWOLZ-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 238000010189 synthetic method Methods 0.000 title abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 86
- 239000002904 solvent Substances 0.000 claims abstract description 83
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 46
- -1 alkynyl oxime ether Chemical compound 0.000 claims abstract description 31
- 239000000758 substrate Substances 0.000 claims abstract description 8
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 8
- 239000011593 sulfur Substances 0.000 claims abstract description 8
- 239000003513 alkali Substances 0.000 claims abstract description 6
- 238000003756 stirring Methods 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 153
- 239000000706 filtrate Substances 0.000 claims description 73
- 239000000047 product Substances 0.000 claims description 33
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 27
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 27
- 239000003480 eluent Substances 0.000 claims description 27
- 239000000741 silica gel Substances 0.000 claims description 27
- 229910002027 silica gel Inorganic materials 0.000 claims description 27
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 26
- 238000001035 drying Methods 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 16
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 9
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 8
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 8
- 238000000605 extraction Methods 0.000 claims description 8
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 7
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 4
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 4
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 3
- 125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 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 3
- 238000002386 leaching Methods 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims 2
- 238000003786 synthesis reaction Methods 0.000 claims 2
- 238000002156 mixing Methods 0.000 claims 1
- HCSCWJCZRCSQFA-UHFFFAOYSA-N 1-methylpyrrolidin-2-one;hydrate Chemical compound O.CN1CCCC1=O HCSCWJCZRCSQFA-UHFFFAOYSA-N 0.000 abstract description 28
- 230000008901 benefit Effects 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 3
- 230000009965 odorless effect Effects 0.000 abstract description 2
- 125000000524 functional group Chemical group 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 84
- 239000007788 liquid Substances 0.000 description 36
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- 238000001816 cooling Methods 0.000 description 25
- 239000003208 petroleum Substances 0.000 description 25
- 238000004809 thin layer chromatography Methods 0.000 description 25
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 description 21
- 238000005160 1H NMR spectroscopy Methods 0.000 description 21
- 238000004983 proton decoupled 13C NMR spectroscopy Methods 0.000 description 21
- 239000007787 solid Substances 0.000 description 20
- 238000001291 vacuum drying Methods 0.000 description 19
- 238000001514 detection method Methods 0.000 description 17
- 239000012295 chemical reaction liquid Substances 0.000 description 9
- 239000005864 Sulphur Substances 0.000 description 7
- YECVQOULKHBGEN-UHFFFAOYSA-N 1,3-diphenylprop-2-yn-1-one Chemical compound C=1C=CC=CC=1C(=O)C#CC1=CC=CC=C1 YECVQOULKHBGEN-UHFFFAOYSA-N 0.000 description 4
- INTMRVMKKHEXEY-UHFFFAOYSA-N 4-[(3,5-diphenyl-1,2-thiazol-4-yl)disulfanyl]-3,5-diphenyl-1,2-thiazole Chemical compound C1(=CC=CC=C1)C1=NSC(=C1SSC=1C(=NSC=1C1=CC=CC=C1)C1=CC=CC=C1)C1=CC=CC=C1 INTMRVMKKHEXEY-UHFFFAOYSA-N 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- 150000002019 disulfides Chemical class 0.000 description 2
- AUZONCFQVSMFAP-UHFFFAOYSA-N disulfiram Chemical compound CCN(CC)C(=S)SSC(=S)N(CC)CC AUZONCFQVSMFAP-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000005265 energy consumption Methods 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- ZDRRIRUAESZNIH-BZGUUIOASA-N (2s)-1-[(4r,7s,10s,13s,16s,19r)-19-amino-7-(2-amino-2-oxoethyl)-13-[(2s)-butan-2-yl]-10-[(1r)-1-hydroxyethyl]-16-[(4-hydroxyphenyl)methyl]-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carbonyl]-n-[(2s)-1-[(2-amino-2-oxoethyl)amino]- Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@H](N)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)[C@@H](C)O)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZDRRIRUAESZNIH-BZGUUIOASA-N 0.000 description 1
- PUDHBTGHUJUUFI-SCTWWAJVSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-n-[(2s,3r)-1-amino-3-hydroxy-1-oxobutan-2-yl]-19-[[(2r)-2-amino-3-naphthalen-2-ylpropanoyl]amino]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5,8,11,14,17-p Chemical compound C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1 PUDHBTGHUJUUFI-SCTWWAJVSA-N 0.000 description 1
- WNOROPMWJWMDPA-UHFFFAOYSA-N 1,1-bis(sulfanylidene)-1,2-thiazole Chemical compound S1(N=CC=C1)(=S)=S WNOROPMWJWMDPA-UHFFFAOYSA-N 0.000 description 1
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical compound NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 1
- PIMAGHUGARRUIS-UHFFFAOYSA-N 1-(4-bromophenyl)-3-phenylprop-2-yn-1-one Chemical compound C1=CC(Br)=CC=C1C(=O)C#CC1=CC=CC=C1 PIMAGHUGARRUIS-UHFFFAOYSA-N 0.000 description 1
- URMSXHVINBWJPQ-UHFFFAOYSA-N 1-(4-ethylphenyl)-3-phenylprop-2-yn-1-one Chemical compound C1=CC(CC)=CC=C1C(=O)C#CC1=CC=CC=C1 URMSXHVINBWJPQ-UHFFFAOYSA-N 0.000 description 1
- PFIKCDNZZJYSMK-UHFFFAOYSA-N 1-cyclohexyl-3-phenylprop-2-yn-1-one Chemical compound C1CCCCC1C(=O)C#CC1=CC=CC=C1 PFIKCDNZZJYSMK-UHFFFAOYSA-N 0.000 description 1
- CEWWIRXHALSUSW-UHFFFAOYSA-N 3-(4-methoxyphenyl)-4-[[3-(4-methoxyphenyl)-5-phenyl-1,2-thiazol-4-yl]disulfanyl]-5-phenyl-1,2-thiazole Chemical compound COC1=CC=C(C=C1)C1=NSC(=C1SSC=1C(=NSC=1C1=CC=CC=C1)C1=CC=C(C=C1)OC)C1=CC=CC=C1 CEWWIRXHALSUSW-UHFFFAOYSA-N 0.000 description 1
- YZKVKHSDZCOEBR-UHFFFAOYSA-N 3-(4-tert-butylphenyl)-1-phenylprop-2-yn-1-one Chemical compound C1=CC(C(C)(C)C)=CC=C1C#CC(=O)C1=CC=CC=C1 YZKVKHSDZCOEBR-UHFFFAOYSA-N 0.000 description 1
- RGJCNXPKDLMKIW-UHFFFAOYSA-N 3-cyclohexyl-4-[(3-cyclohexyl-5-phenyl-1,2-thiazol-4-yl)disulfanyl]-5-phenyl-1,2-thiazole Chemical compound C1(CCCCC1)C1=NSC(=C1SSC=1C(=NSC=1C1=CC=CC=C1)C1CCCCC1)C1=CC=CC=C1 RGJCNXPKDLMKIW-UHFFFAOYSA-N 0.000 description 1
- USOOSBLWANZOSB-UHFFFAOYSA-N 5-(1,3-thiazol-5-yldisulfanyl)-1,3-thiazole Chemical compound S1C=NC=C1SSC1=CN=CS1 USOOSBLWANZOSB-UHFFFAOYSA-N 0.000 description 1
- IBIHUZACQFJUHW-UHFFFAOYSA-N 5-(3-chlorophenyl)-4-[[5-(3-chlorophenyl)-3-phenyl-1,2-thiazol-4-yl]disulfanyl]-3-phenyl-1,2-thiazole Chemical compound ClC=1C=C(C=CC=1)C1=C(C(=NS1)C1=CC=CC=C1)SSC=1C(=NSC=1C1=CC(=CC=C1)Cl)C1=CC=CC=C1 IBIHUZACQFJUHW-UHFFFAOYSA-N 0.000 description 1
- QXGCFWYZOJXWMR-UHFFFAOYSA-N 5-(4-chlorophenyl)-4-[[5-(4-chlorophenyl)-3-phenyl-1,2-thiazol-4-yl]disulfanyl]-3-phenyl-1,2-thiazole Chemical compound ClC1=CC=C(C=C1)C1=C(C(=NS1)C1=CC=CC=C1)SSC=1C(=NSC=1C1=CC=C(C=C1)Cl)C1=CC=CC=C1 QXGCFWYZOJXWMR-UHFFFAOYSA-N 0.000 description 1
- PVLNCDRFUBXQIJ-UHFFFAOYSA-N 5-(4-methoxyphenyl)-4-[[5-(4-methoxyphenyl)-3-phenyl-1,2-thiazol-4-yl]disulfanyl]-3-phenyl-1,2-thiazole Chemical compound COC1=CC=C(C=C1)C1=C(C(=NS1)C1=CC=CC=C1)SSC=1C(=NSC=1C1=CC=C(C=C1)OC)C1=CC=CC=C1 PVLNCDRFUBXQIJ-UHFFFAOYSA-N 0.000 description 1
- XVLXOZJDOXWFLS-UHFFFAOYSA-N 5-(4-tert-butylphenyl)-4-[[5-(4-tert-butylphenyl)-3-phenyl-1,2-thiazol-4-yl]disulfanyl]-3-phenyl-1,2-thiazole Chemical compound C(C)(C)(C)C1=CC=C(C=C1)C1=C(C(=NS1)C1=CC=CC=C1)SSC=1C(=NSC=1C1=CC=C(C=C1)C(C)(C)C)C1=CC=CC=C1 XVLXOZJDOXWFLS-UHFFFAOYSA-N 0.000 description 1
- 108010000437 Deamino Arginine Vasopressin Proteins 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical class S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- 102000005157 Somatostatin Human genes 0.000 description 1
- 108010056088 Somatostatin Proteins 0.000 description 1
- 108010047196 Urofollitropin Proteins 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 229950003476 aminothiazole Drugs 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- NFLWUMRGJYTJIN-NXBWRCJVSA-N desmopressin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSCCC(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(N)=O)=O)CCC(=O)N)C1=CC=CC=C1 NFLWUMRGJYTJIN-NXBWRCJVSA-N 0.000 description 1
- 229960004281 desmopressin Drugs 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 229960002563 disulfiram Drugs 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 150000002390 heteroarenes Chemical class 0.000 description 1
- 238000010505 homolytic fission reaction Methods 0.000 description 1
- 125000004500 isothiazol-4-yl group Chemical group S1N=CC(=C1)* 0.000 description 1
- 108010021336 lanreotide Proteins 0.000 description 1
- 229960002437 lanreotide Drugs 0.000 description 1
- 238000010327 methods by industry Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 150000005838 radical anions Chemical class 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- OHRURASPPZQGQM-GCCNXGTGSA-N romidepsin Chemical compound O1C(=O)[C@H](C(C)C)NC(=O)C(=C/C)/NC(=O)[C@H]2CSSCC\C=C\[C@@H]1CC(=O)N[C@H](C(C)C)C(=O)N2 OHRURASPPZQGQM-GCCNXGTGSA-N 0.000 description 1
- OHRURASPPZQGQM-UHFFFAOYSA-N romidepsin Natural products O1C(=O)C(C(C)C)NC(=O)C(=CC)NC(=O)C2CSSCCC=CC1CC(=O)NC(C(C)C)C(=O)N2 OHRURASPPZQGQM-UHFFFAOYSA-N 0.000 description 1
- 229960003452 romidepsin Drugs 0.000 description 1
- 108010091666 romidepsin Proteins 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- SRRKNRDXURUMPP-UHFFFAOYSA-N sodium disulfide Chemical compound [Na+].[Na+].[S-][S-] SRRKNRDXURUMPP-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 description 1
- 229960000553 somatostatin Drugs 0.000 description 1
- FNKUJDADVODZOY-UHFFFAOYSA-N sulfanyl thiohypochlorite Chemical compound SSCl FNKUJDADVODZOY-UHFFFAOYSA-N 0.000 description 1
- 150000003461 sulfonyl halides Chemical class 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 229960004371 urofollitropin Drugs 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
- C07D275/03—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a synthetic method of isothiazole-4-yl disulfide derivatives, which comprises the following steps: taking alkynyl oxime ether as a substrate, elemental sulfur as a sulfur source, 1, 8-diazabicycloundecen-7-ene as alkali and NMP-H2O(5:1,V:V) As a solvent, stirring and reacting at 100-120 ℃ for 12 hours. The invention uses odorless, easily available and cheap elemental sulfur as a sulfur source, and has the advantages of simple and easily available raw materials, simple reaction operation, relatively mild conditions, wide substrate universality, higher yield and good functional group compatibility.
Description
Technical Field
The present invention relates to a process for the preparation of isothiazol-4-yl disulfide derivatives.
Background
Disulfide-bond scaffolds are widely present in natural products and drug molecules, such as the drugs romidepsin, somatostatin, urofollitropin, disulfiram, lanreotide and desmopressin, among others. Therefore, how to synthesize disulfide efficiently has attracted much attention for decades. Traditionally, oxidation of thiols is the classical pathway for the construction of symmetric disulfide bonds (J.Am.chem.Soc.2002,124, 5626). Alkyl halide and disodium disulfide (Na)2S2) Or cross-coupling of elemental sulfur and reduction of sulfonyl halides can also create S-S bonds (j.am.chem.soc.2018,140, 30; synth Commun.1995,25,3573; J.chem.Res.2006, 547). In addition, disulfide dichloride (S)2Cl2) Reactions with olefins, heteroarenes or aryl zinc halides can also be used to prepare disulfides (j.org.chem.1969,34,3991; synlett2005, 1185); for example, the Zia-ur-Rehman' S group synthesized 5-thiazolyl disulfide (chem. pharm. Bull.2007,55,1014) with antibacterial activity in 2007 with aminothiazole and S2Cl 2. However, these conversions have the disadvantages of using mercaptans with unpleasant odor or unstable disulfides dichloride, and of very limited reaction substrates.
Disclosure of Invention
Aiming at the defects existing in the prior stage, the invention provides the method for preparing the isothiazole-4-yl disulfide derivative, which takes alkynyl oxime ether as a reaction raw material and elemental sulfur as a sulfur source, and has the advantages of simple technical process, high yield, less pollution, environmental protection and safety.
In order to achieve the purpose, the invention adopts the technical scheme that: a method for synthesizing isothiazol-4-yl disulfide derivatives, comprising the steps of: taking alkynyl oxime ether as a substrate, elemental sulfur as a sulfur source, 1, 8-diazabicycloundecen-7-ene as alkali and NMP-H2O is mixed as a solvent at a volume ratio of 5:1 at 100 ℃Stirring the mixture at 120 ℃ for 12 hours to react, wherein the chemical reaction formula is as follows:
the-R is one of phenyl, 4-methylphenyl, 2-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 3-chlorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 2-naphthyl, 2-thienyl and cyclohexyl;
and the-Ar is one of phenyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 4-tert-butylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl and 4-trifluoromethylphenyl.
The preparation method adopted by the invention is that the isothiazole-4-yl disulfide derivative is synthesized by the reaction of alkynyl oxime ether and elemental sulfur under the promotion of alkali, and the odorless, easily available and cheap elemental sulfur is used as a sulfur source, so that the process is simple, special instruments or modes are not needed, the method is very suitable for the operation of people in the field, and has the advantages of simple and convenient operation, easily available products and the like.
According to a further configuration of the present invention, the amount of the elemental sulfur is 2 equivalents of the alkynyl oxime ether.
In a further development of the invention, the base is used in an amount of 3 equivalents of the alkynyloxime ether.
The method is further provided, after the reaction is finished, the reaction solution is filtered, washed by saturated sodium chloride solution, dried by anhydrous sodium sulfate after ethyl acetate extraction, the filtrate is subjected to solvent removal by a rotary evaporator to obtain a residue, the residue is subjected to column layer separation by a silica gel column and is leached by eluent, the effluent containing the target product is collected, the effluent is combined, and the solvent is removed by vacuum concentration to obtain the target product.
The method can directly synthesize the target product, does not need to separate intermediate products, can obtain the target product only by stirring and reacting under normal pressure, has the highest yield of 89 percent, greatly simplifies process engineering, reduces energy consumption and has the advantage of high yield; in addition, the waste solution is less in the reaction process, and other polluted gases and liquid are not discharged, so that the method reduces the discharge of the waste solution, and has the advantages of protecting the environment and ensuring the health of operators; in addition, a series of isothiazol-4-yl disulfide derivatives can be prepared, and the method has strong substrate universality. Therefore, the invention fills the blank of the method for preparing the isothiazole-4-yl disulfide derivative at the present stage, promotes the development of the polysubstituted isothiazole-4-yl disulfide derivative and provides a powerful guarantee for developing the medicament containing the isothiazole-4-yl disulfide derivative.
The mechanism of the invention is as follows: first, S8Reaction with the base DBU (Chinese name: 1, 8-diazabicycloundec-7-ene) to produce the trithio radical species (S)3 ·-) And then attack carbon-carbon triple bonds to form the radical anion intermediate a. Subsequently, another molecule of S3 ·-Further reacting with the intermediate A to generate a divalent anion B. Subsequent homolytic cleavage of the dianion B releases S2 ·-And a disulfide free radical C which is subjected to intermolecular free radical dimerization to obtain an intermediate D, and finally, intramolecular demethoxylation to obtain the target isothiazole disulfide 2. Reaction mechanism the chemical reaction formula is as follows:
Detailed Description
The invention discloses a synthetic method of isothiazole-4-yl disulfide derivatives, which comprises the following steps: taking alkynyl oxime ether as a substrate, elemental sulfur as a sulfur source, 1, 8-diazabicycloundecen-7-ene (DBU) as alkali and NMP-H2O (5:1, V: V) is used as a solvent, and the mixture is stirred and reacted for 12 hours at the temperature of 100-120 ℃; the chemical reaction formula is as follows:
the-R is one of phenyl, 4-methylphenyl, 2-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 3-chlorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 2-naphthyl, 2-thienyl and cyclohexyl;
the-Ar is one of phenyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 4-tert-butylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl and 4-trifluoromethylphenyl;
after the reaction is finished, cooling, filtering the reaction solution to obtain a filtrate, washing with a saturated sodium chloride solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, removing the solvent from the filtrate with a rotary evaporator to obtain a residue, eluting the residue with an eluent prepared from petroleum ether and ethyl acetate according to the volume ratio of 30:1 through a silica gel column, collecting the effluent according to the actual gradient, detecting by TLC, combining the effluent containing the target product, rotating the combined effluent with the rotary evaporator to remove the solvent, and finally drying in vacuum to obtain the target product.
The first embodiment is as follows: 47.0 mg (0.2mmol) of 1, 3-diphenylprop-2-yn-1-one o-methyloxime, 102.4 mg (0.4mmol) of elemental sulfur, 91.2 mg (0.6mmol) of 1, 8-diazabicycloundec-7-ene (DBU) were added to 2mL of the solvent NMP-H2O (5:1, V: V). The reaction was stirred at 120 ℃ for 12 hours. After the reaction is finished, cooling is carried out, the reaction solution is filtered to obtain filtrate, the filtrate is washed by saturated sodium chloride solution, ethyl acetate is used for extracting and then is dried by anhydrous sodium sulfate, the filtrate is used for removing the solvent by a rotary evaporator to obtain a residue, the residue is eluted by silica gel column by eluent prepared by petroleum ether and ethyl acetate according to the volume ratio of 30:1, the effluent is collected according to the actual gradient, the effluent containing the target product is combined by TLC detection, the combined effluent is rotated by the rotary evaporator to remove the solvent, and vacuum drying is carried out to obtain yellow solid 1, 2-bis (3, 5-diphenylisothiazole-4-yl) disulfane 43.4 mg with the yield of 81%.1H NMR(400MHz,CDCl3)δ7.54-7.52(m,4H),7.49-7.40(m,12H),7.23-7.21(m,4H)；13C{1H}NMR(125MHz,CDCl3)δ171.9,170.6,135.0,130.2,129.7,129.09,129.06,128.8,128.1,123.2.HRMS(ESI)Calcd for C30H21N2S4 +([M+H]+)537.0582,found 537.0568。
The second embodiment is as follows: 49.8 mg (0.2mmol) of 1-phenyl-3- (p-tolyl) propyl-2-yn-1-one oxime, 102.4 mg (0.4mmol) of elemental sulphur, 91.2 mg (0.6mmol) of 1, 8-diazabicycloundec-7-ene (DBU) are added to 2mL of the solvent NMP-H2O (5:1, V: V). The reaction was stirred at 120 ℃ for 12 hours. After the reaction is finished, cooling is carried out, the reaction liquid is filtered to obtain filtrate, the filtrate is washed by saturated sodium chloride solution, ethyl acetate is used for extracting, then anhydrous sodium sulfate is used for drying, the filtrate is used for removing the solvent by a rotary evaporator to obtain residue, the residue is eluted by silica gel column through eluent prepared by petroleum ether and ethyl acetate according to the volume ratio of 30:1, effluent liquid is collected according to actual gradient, TLC detection is carried out, effluent liquid containing the target product is combined, the solvent is removed by the rotary evaporator through rotation of the combined effluent liquid, and vacuum drying is carried out to obtain 47.4 mg of 1, 2-bis (3-phenyl-5- (p-tolyl) isothiazol-4-yl) dithioane as yellow solid with the yield of 84%.1H NMR(400MHz,CDCl3)δ7.51-7.49(m,4H),7.43-7.36(m,6H),7.21(d,J＝8.0Hz,4H),7.12(d,J＝8.0Hz,4H),2.45(s,6H)；13C{1H}NMR(125MHz,CDCl3)δ172.0,170.6,140.0,135.1,129.5,129.09,129.06,128.9,128.1,127.4,123.0,21.5.HRMS(ESI)Calcd for C32H25N2S4 +([M+H]+)565.0895,found 565.0896。
The third concrete embodiment: 49.8 mg (0.2mmol) of 1-phenyl-3- (m-tolyl) propyl-2-yn-1-one oxime, 102.4 mg (0.4mmol) of elemental sulfur, 91.2 mg (0.6mmol) of 1, 8-diazabicycloundec-7-ene (DBU) were added to 2mL of the solvent NMP-H2O (5:1, V: V). The reaction was stirred at 120 ℃ for 12 hours. Cooling after the reaction is finished, filtering the reaction liquid to obtain filtrate, washing with saturated sodium chloride solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, removing the solvent from the filtrate with a rotary evaporator to obtain a residue, eluting the residue with an eluent prepared from petroleum ether and ethyl acetate according to the volume ratio of 30:1 through a silica gel column, collecting the effluent according to the actual gradient, detecting by TLC, combining the effluent containing the target product, removing the solvent from the combined effluent by rotating the rotary evaporator, and drying in vacuum to obtain a yellow solid 1, 2-bis (3-phenyl-5- (p-tolyl) -5) Isothiazol-4-yl) disulfane 44.6 mg, yield 79%.1H NMR(400MHz,CDCl3)δ7.54-7.52(m,4H),7.44-7.38(m,6H),7.33-7.27(m,4H),7.03-7.01(m,4H),2.42(s,6H)；13C{1H}NMR(125MHz,CDCl3)δ172.1,170.5,138.4,135.0,130.4,130.0,129.7,129.02,128.99,128.6,128.0,126.1,123.0,21.5.HRMS(ESI)Calcd for C32H25N2S4 +([M+H]+)565.0895,found 565.0894。
The fourth concrete embodiment: 49.8 mg (0.2mmol) of 1-phenyl-3- (o-tolyl) propyl-2-yn-1-one oxime, 102.4 mg (0.4mmol) of elemental sulphur, 91.2 mg (0.6mmol) of 1, 8-diazabicycloundec-7-ene (DBU) are added to 2mL of the solvent NMP-H2O (5:1, V: V). The reaction was stirred at 120 ℃ for 12 hours. After the reaction is finished, cooling is carried out, the reaction liquid is filtered to obtain filtrate, the filtrate is washed by saturated sodium chloride solution, ethyl acetate is used for extracting, then anhydrous sodium sulfate is used for drying, the filtrate is used for removing the solvent by a rotary evaporator to obtain residue, the residue is eluted by silica gel column through eluent prepared by petroleum ether and ethyl acetate according to the volume ratio of 30:1, effluent liquid is collected according to actual gradient, TLC detection is carried out, effluent liquid containing a target product is combined, the combined effluent liquid is used for removing the solvent by the rotary evaporator in a rotating mode, vacuum drying is carried out to obtain yellow liquid 1, 2-bis (3-phenyl-5- (o-tolyl) isothiazole-4-yl) dithioane 23.7 mg, and the yield is 42%.1H NMR(400MHz,CDCl3)δ7.52-7.50(m,4H),7.42-7.33(m,8H),7.27-7.25(m,2H),7.18-7.14(m,2H),6.55-6.53(m,2H),2.01(s,6H)；13C{1H}NMR(125MHz,CDCl3)δ171.8,169.5,136.7,134.9,130.33,130.25,129.7,129.6,129.2,128.9,128.2,126.0,125.7,20.2.HRMS(ESI)Calcd for C32H25N2S4 +([M+H]+)565.0895,found 565.0895。
The fifth concrete embodiment: 59.2 mg (0.2mmol) of (3- (4- (tert-butyl) phenyl) -1-phenylpropan-2-yn-1-one o-methyloxime, 102.4 mg (0.4mmol) of elemental sulphur, 91.2 mg (0.6mmol) of 1, 8-diazabicycloundec-7-ene (DBU) are added to 2mL of the solvent NMP-H2O (5:1, V: V). The reaction was stirred at 120 ℃ for 12 hours. Cooling after the reaction is finishedHowever, the reaction solution was filtered to obtain a filtrate, which was washed with a saturated sodium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the filtrate was subjected to solvent removal using a rotary evaporator to obtain a residue, which was eluted through a silica gel column with an eluent prepared from petroleum ether and ethyl acetate at a volume ratio of 30:1, the eluates were collected according to a practical gradient, checked by TLC, the eluates containing the target product were combined, the combined eluates were subjected to rotary evaporator to remove the solvent, and vacuum-dried to obtain 53.1 mg of 1, 2-bis (5- (4- (tert-butyl) phenyl) -3-phenylisothiazol-4-yl) disulfane as a yellow solid in 82% yield.1H NMR(400MHz,CDCl3)δ7.51-7.49(m,4H),7.44-7.38(m,10H),7.17(d,J＝8.0Hz,4H),1.40(s,18H)；13C{1H}NMR(125MHz,CDCl3)δ172.1,170.6,152.9,135.1,129.1,129.0,128.8,128.0,127.3,125.8,122.8,35.0,31.4.HRMS(ESI)Calcd for C38H37N2S4 +([M+H]+)649.1834,found 649.1843。
The sixth specific embodiment: 53.0 mg (0.2mmol) of 3 (4-methoxyphenyl) -1-phenyl-2-yn-1-one oxime, 102.4 mg (0.4mmol) of elemental sulfur, 91.2 mg (0.6mmol) of 1, 8-diazabicycloundecen-7-ene (DBU) are added to 2mL of the solvent NMP-H2O (5:1, V: V). The reaction was stirred at 120 ℃ for 12 hours. After the reaction is finished, cooling is carried out, the reaction liquid is filtered to obtain filtrate, the filtrate is washed by saturated sodium chloride solution, ethyl acetate is used for extracting and then is dried by anhydrous sodium sulfate, the filtrate is used for removing the solvent by a rotary evaporator to obtain residue, the residue is eluted by silica gel column by eluent prepared by petroleum ether and ethyl acetate according to the volume ratio of 30:1, the effluent is collected according to actual gradient and detected by TLC, the effluent containing the target product is combined, the combined effluent is rotated by the rotary evaporator to remove the solvent, and vacuum drying is carried out to obtain yellow solid 1, 2-bis (5- (4-methoxyphenyl) -3-phenylisothiazol-4-yl) disulfane 44.7 mg with the yield of 75%.1H NMR(400MHz,CDCl3)δ7.51-7.49(m,4H),7.42-7.36(m,6H),7.21(d,J＝8.8Hz,4H),6.92(d,J＝8.8Hz,4H),3.89(s,6H)；13C{1H}NMR(125MHz,CDCl3)δ171.8,170.7,160.9,135.2,130.4,129.1,129.0,128.1,122.7,122.5,114.3,55.6.HRMS(ESI)Calcd for C32H25N2O2S4 +([M+H]+)597.0819,found 597.0819。
The seventh specific embodiment: 50.6 mg (0.2mmol) of 3 (4-fluorophenyl) -1-phenyl-2-yn-1-one oxime, 102.4 mg (0.4mmol) of elemental sulfur, 91.2 mg (0.6mmol) of 1, 8-diazabicycloundecen-7-ene (DBU) are added to 2mL of the solvent NMP-H2O (5:1, V: V). The reaction was stirred at 120 ℃ for 12 hours. After the reaction is finished, cooling is carried out, the reaction solution is filtered to obtain filtrate, the filtrate is washed by saturated sodium chloride solution, ethyl acetate is used for extraction, then anhydrous sodium sulfate is used for drying, the filtrate is used for removing the solvent by a rotary evaporator to obtain a residue, the residue is eluted by silica gel column through eluent prepared by petroleum ether and ethyl acetate according to the volume ratio of 30:1, effluent liquid is collected according to actual gradient, TLC detection is carried out, effluent liquid containing a target product is combined, the combined effluent liquid is used for removing the solvent by the rotary evaporator in a rotating mode, vacuum drying is carried out to obtain 30.3 mg of 1, 2-bis (5- (4-fluorophenyl) -3-phenylisothiazole-4-yl) dithioane as a yellow solid, and the yield is 53%.1H NMR(400MHz,CDCl3)δ7.50-7.48(m,4H),7.44-7.37(m,6H),7.22-7.18(m,4H),7.13-7.08(m,4H)；13C{1H}NMR(125MHz,CDCl3)δ170.8,170.6,163.6(d,JC-F＝250.0Hz),134.8,130.9,129.2,129.0,128.2,126.2,123.2,116.0(d,JC-F＝21.3Hz).HRMS(ESI)Calcd for C30H19F2N2S4 +([M+H]+)573.0394,found 573.0381。
The eighth embodiment: 53.8 mg (0.2mmol) of 3- (4-chlorophenyl) -1-phenyl-2-yn-1-one o-methyloxime, 102.4 mg (0.4mmol) of elemental sulfur, 91.2 mg (0.6mmol) of 1, 8-diazabicycloundec-7-ene (DBU) are added to 2mL of the solvent NMP-H2O (5:1, V: V). The reaction was stirred at 120 ℃ for 12 hours. Cooling after the reaction is finished, filtering the reaction solution to obtain filtrate, washing the filtrate with saturated sodium chloride solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, removing the solvent from the filtrate with a rotary evaporator to obtain residue, leaching the residue with silica gel column by using eluent prepared from petroleum ether and ethyl acetate according to the volume ratio of 30:1, and leaching according to actual gradientThe eluates were collected, checked by TLC, combined, and the combined eluates were subjected to rotary evaporation to remove the solvent, followed by vacuum drying to obtain 39.9 mg of 1, 2-bis (5- (4-chlorophenyl) -3-phenylisothiazol-4-yl) disulfane as a yellow solid in 66% yield.1H NMR(400MHz,CDCl3)δ7.49-7.47(m,4H),7.44-7.37(m,10H),7.15-7.12(m,4H)；13C{1H}NMR(125MHz,CDCl3)δ170.61,170.57,136.2,134.7,130.2,129.3,129.2,129.0,128.5,128.2,123.3。
The specific embodiment is nine: 47.0 mg (0.2mmol) of (Z) -1-phenyl-3- (4- (trifluoromethyl) phenyl) propyl-2-yn-1-one oxime, 102.4 mg (0.4mmol) of elemental sulfur, 91.2 mg (0.6mmol) of 1, 8-diazabicycloundec-7-ene (DBU) are added to 2mL of the solvent NMP-H2O (5:1, V: V). The reaction was stirred at 120 ℃ for 12 hours. After the reaction is finished, cooling is carried out, the reaction solution is filtered to obtain filtrate, the filtrate is washed by saturated sodium chloride solution, ethyl acetate is used for extraction, then anhydrous sodium sulfate is used for drying, the filtrate is used for removing the solvent by a rotary evaporator to obtain a residue, the residue is eluted by silica gel column through eluent prepared by petroleum ether and ethyl acetate according to the volume ratio of 30:1, effluent liquid is collected according to actual gradient, TLC detection is carried out, effluent liquid containing a target product is combined, the combined effluent liquid is used for removing the solvent by the rotary evaporator in a rotating mode, and vacuum drying is carried out to obtain yellow solid 1, 2-bis (3-phenyl-5- (4- (trifluoromethyl) phenyl) isothiazol-4-yl) dithioane 23.5 mg with the yield of 35%.1H NMR(400MHz,CDCl3)δ7.68-7.66(m,4H),7.47-7.38(m,10H),7.29-7.27(m,4H).；13C{1H}NMR(125MHz,CDCl3)δ170.5,170.2,134.4,133.5,131.7(q,JC-F＝32.5Hz),129.42,129.39,128.9,128.3,125.8,123.9(q,JC-F＝270Hz),123.8.HRMS(ESI)Calcd for C32H18F6N2Na S4 +([M+Na]+)695.0149,found 695.0126。
The specific embodiment ten: 49.8 mg (0.2mmol) of 3-phenyl-1- (p-tolyl) propyl-2-yn-1 one-O-methyloxime, 102.4 mg (0.4mmol) of elemental sulphur, 91.2 mg (0.6mmol) of 1, 8-diazabicycloundec-7-ene (DBU) are added to 2mL of the solvent NMP-H2O (5:1, V: V). The reaction was stirred at 120 ℃ for 12 hours. After the reaction is finished, cooling is carried out, the reaction liquid is filtered to obtain filtrate, the filtrate is washed by saturated sodium chloride solution, ethyl acetate is used for extracting, then anhydrous sodium sulfate is used for drying, the filtrate is used for removing the solvent by a rotary evaporator to obtain residue, the residue is eluted by silica gel column through eluent prepared by petroleum ether and ethyl acetate according to the volume ratio of 30:1, effluent liquid is collected according to actual gradient, TLC detection is carried out, effluent liquid containing a target product is combined, the solvent is removed by the rotary evaporator through rotation, and vacuum drying is carried out to obtain 50.2 mg of 1, 2-bis (5-phenyl-3- (p-tolyl) isothiazol-4-yl) dithioane as yellow solid with the yield of 89%.1H NMR(400MHz,CDCl3)δ7.45-7.37(m,10H),7.20-7.18(m,8H),2.43(m,6H)；13C{1H}NMR(125MHz,CDCl3)δ171.7,170.6,139.0,132.3,130.2,129.6,129.0,128.9,128.82,128.75,123.2,21.5.HRMS(ESI)Calcd for C32H25N2S4 +([M+H]+)565.0895,found 565.0907。
The first specific embodiment: 49.8 mg (0.2mmol) of (Z) -3-phenyl-1- (O-tolyl) propyl-2-yn-1-one-O-methyloxime, 102.4 mg (0.4mmol) of elemental sulphur, 91.2 mg (0.6mmol) of 1, 8-diazabicycloundec-7-ene (DBU) are added to 2mL of the solvent NMP-H2O (5:1, V: V). The reaction was stirred at 120 ℃ for 12 hours. After the reaction is finished, cooling is carried out, the reaction liquid is filtered to obtain filtrate, the filtrate is washed by saturated sodium chloride solution, ethyl acetate is used for extracting, then anhydrous sodium sulfate is used for drying, the filtrate is used for removing the solvent by a rotary evaporator to obtain residue, the residue is eluted by silica gel column through eluent prepared by petroleum ether and ethyl acetate according to the volume ratio of 30:1, effluent liquid is collected according to actual gradient, TLC detection is carried out, effluent liquid containing a target product is combined, the combined effluent liquid is used for removing the solvent by the rotary evaporator in a rotating mode, vacuum drying is carried out to obtain yellow liquid 1, 2-bis (5-phenyl-3- (o-tolyl) isothiazole-4-yl) dithioane 34.4 mg, and the yield is 61%.1H NMR(400MHz,CDCl3)δ7.46-7.39(m,6H),7.34-7.27(m,6H),7.23-7.21(m,2H),7.18-7.15(m,2H),6.80-6.79(m,2H),2.03(s,6H)；13C{1H}NMR(125MHz,CDCl3)δ172.8,170.4,136.8,135.1,130.13,130.06,130.0,129.9,129.1,128.91,128.89,125.4,125.2,19.9.HRMS(ESI)Calcd for C32H25N2S4 +([M+H]+)565.0895,found 565.0918。
The specific example twelve: 52.6 mg (0.2mmol) of 1- (4-ethylphenyl) -3-phenylprop-2-yn-1-one o-methyloxime, 102.4 mg (0.4mmol) of elemental sulphur, 91.2 mg (0.6mmol) of 1, 8-diazabicycloundec-7-ene (DBU) are added to 2mL of the solvent NMP-H2O (5:1, V: V). The reaction was stirred at 120 ℃ for 12 hours. After the reaction is finished, cooling is carried out, the reaction solution is filtered to obtain filtrate, the filtrate is washed by saturated sodium chloride solution, ethyl acetate is used for extraction, then anhydrous sodium sulfate is used for drying, the filtrate is used for removing the solvent by a rotary evaporator to obtain residue, the residue is eluted by silica gel column through eluent prepared by petroleum ether and ethyl acetate according to the volume ratio of 30:1, effluent liquid is collected according to actual gradient, TLC detection is carried out, effluent liquid containing a target product is combined, the combined effluent liquid is used for removing the solvent by the rotary evaporator in a rotating mode, and vacuum drying is carried out to obtain yellow solid 1, 2-bis (3- (4-ethyl phenyl) -5-phenyl isothiazole-4-yl) dithioane 42.6 mg with the yield of 72%.1H NMR(400MHz,CDCl3)δ7.47-7.38(m,10H),7.22-7.20(m,8H),2.72(q,J＝7.6Hz,4H),1.30(t,J＝7.6Hz,6H)；13C{1H}NMR(125MHz,CDCl3)δ171.8,170.7,145.2,132.5,130.3,129.7,129.1,129.0,128.8,127.7,123.2,28.9,15.5.HRMS(ESI)Calcd for C34H29N2S4 +([M+H]+)593.1208,found 593.1219。
The specific example thirteen: 53.0 mg (0.2mmol) of 1 (4-methoxyphenyl) -3-phenyl-2-yn-1-one oxime, 102.4 mg (0.4mmol) of elemental sulfur, 91.2 mg (0.6mmol) of 1, 8-diazabicycloundecen-7-ene (DBU) are added to 2mL of the solvent NMP-H2O (5:1, V: V). The reaction was stirred at 120 ℃ for 12 hours. Cooling after the reaction is finished, filtering the reaction solution to obtain filtrate, washing the filtrate with saturated sodium chloride solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, removing the solvent from the filtrate with a rotary evaporator to obtain residue, and introducing the residue into an eluent prepared from petroleum ether and ethyl acetate according to the volume ratio of 30:1 through a silica gel columnEluting, collecting effluent according to actual gradient, detecting by TLC, combining the effluent containing the target product, removing the solvent by rotating the combined effluent by a rotary evaporator, and drying in vacuum to obtain 30.4 mg of 1, 2-bis (3- (4-methoxyphenyl) -5-phenylisothiazol-4-yl) disulfane as yellow solid with the yield of 51%.1H NMR(400MHz,CDCl3)δ7.52(d,J＝8.8Hz,4H),7.45-7.37(m,6H),7.20-7.18(m,4H),6.90(d,J＝8.8Hz,4H),3.88(s,6H)；13C{1H}NMR(125MHz,CDCl3)δ171.8,170.0,160.3,130.4,130.3,129.6,129.0,128.8,127.8,122.9,113.6,55.5.HRMS(ESI)Calcd for C32H25N2O2S4 +([M+H]+)597.0793,found 597.0818。
The specific embodiment fourteen: 50.6 mg (0.2mmol) of 1 (4-fluorophenyl) -3-phenyl-2-yn-1-one oxime, 102.4 mg (0.4mmol) of elemental sulfur, 91.2 mg (0.6mmol) of 1, 8-diazabicycloundecen-7-ene (DBU) are added to 2mL of the solvent NMP-H2O (5:1, V: V). The reaction was stirred at 120 ℃ for 12 hours. After the reaction is finished, cooling is carried out, the reaction solution is filtered to obtain filtrate, the filtrate is washed by saturated sodium chloride solution, ethyl acetate is used for extracting, then anhydrous sodium sulfate is used for drying, the filtrate is used for removing the solvent by a rotary evaporator to obtain a residue, the residue is eluted by silica gel column through eluent prepared by petroleum ether and ethyl acetate according to the volume ratio of 30:1, the effluent is collected according to the actual gradient, the effluent containing the target product is combined by TLC detection, the combined effluent is rotated by the rotary evaporator to remove the solvent, and vacuum drying is carried out to obtain 35.5 mg of 1, 2-bis (3- (4-fluorophenyl) -5-phenylisothiazol-4-yl) dithioane as a yellow solid with the yield of 62%.1H NMR(400MHz,CDCl3)δ7.52-7.39(m,10H),7.18-7.16(m,4H),7.09-7.05(m,4H)；13C{1H}NMR(125MHz,CDCl3)δ172.2,169.3,163.4(q,JC-F＝247.5Hz),131.0,130.9,130.0,129.9,129.0,128.9,122.7,115.2(q,JC-F＝21.3Hz).HRMS(ESI)Calcd for C30H19F2N2S4 +([M+H]+)573.0394,found 573.0384。
The specific embodiment fifteen: 53.8 mg (0.2mmol) of 1- (4-Chlorophenyl) -3-phenyl-2-yn-1-one o-methyloxime, 102.4 mg (0.4mmol) of elemental sulfur, 91.2 mg (0.6mmol) of 1, 8-diazabicycloundec-7-ene (DBU) were added to 2mL of the solvent NMP-H2O (5:1, V: V). The reaction was stirred at 120 ℃ for 12 hours. After the reaction is finished, cooling is carried out, the reaction solution is filtered to obtain filtrate, the filtrate is washed by saturated sodium chloride solution, ethyl acetate is used for extraction, then anhydrous sodium sulfate is used for drying, the filtrate is used for removing the solvent by a rotary evaporator to obtain residue, the residue is eluted by silica gel column through eluent prepared by petroleum ether and ethyl acetate according to the volume ratio of 30:1, the effluent is collected according to actual gradient, TLC detection is carried out, the effluent containing the target product is combined, the combined effluent is used for removing the solvent by the rotary evaporator in a rotating way, and vacuum drying is carried out to obtain 41.1 mg of 1, 2-bis (3- (4-chlorphenyl) -5-phenylisothiazole-4-yl) dithioane as yellow solid with the yield of 68%.1H NMR(400MHz,CDCl3)δ7.49-7.34(m,14H),7.18-7.15(m,4H)；13C{1H}NMR(125MHz,CDCl3)δ172.3,169.0,135.4,133.2,130.3,129.9,129.0,128.9,128.4,122.7。
The specific embodiment is sixteen: 53.8 mg (0.2mmol) of 1- (3-chlorophenyl) -3-phenyl-2-yn-1-one o-methyloxime, 102.4 mg (0.4mmol) of elemental sulfur, 91.2 mg (0.6mmol) of 1, 8-diazabicycloundec-7-ene (DBU) are added to 2mL of the solvent NMP-H2O (5:1, V: V). The reaction was stirred at 120 ℃ for 12 hours. After the reaction is finished, cooling is carried out, the reaction liquid is filtered to obtain filtrate, the filtrate is washed by saturated sodium chloride solution, ethyl acetate is used for extracting, then anhydrous sodium sulfate is used for drying, the filtrate is used for removing the solvent by a rotary evaporator to obtain residue, the residue is eluted by silica gel column through eluent prepared by petroleum ether and ethyl acetate according to the volume ratio of 30:1, effluent liquid is collected according to actual gradient, TLC detection is carried out, effluent liquid containing a target product is combined, the combined effluent liquid is used for removing the solvent by the rotary evaporator in a rotating mode, vacuum drying is carried out to obtain yellow liquid 1, 2-bis (5- (3-chlorphenyl) -3-phenylisothiazole-4-yl) disulfane 26.0 mg, and the yield is 43%.1H NMR(400MHz,CDCl3)δ7.52-7.49(m,2H),7.46-7.38(m,10H),7.34-7.30(m,2H),7.18-7.16(m,4H)；13C{1H}NMR(125MHz,CDCl3)δ172.5,168.8,136.4,134.1,130.0,129.8,129.4,129.3,129.0,128.9,127.0,122.8。
Specific example seventeen: 62.6 mg (0.2mmol) of 1- (4-bromophenyl) -3-phenylprop-2-yn-1-one o-methyloxime, 102.4 mg (0.4mmol) of elemental sulfur, 91.2 mg (0.6mmol) of 1, 8-diazabicycloundec-7-ene (DBU) are added to 2mL of the solvent NMP-H2O (5:1, V: V). The reaction was stirred at 120 ℃ for 12 hours. After the reaction is finished, cooling is carried out, the reaction solution is filtered to obtain filtrate, the filtrate is washed by saturated sodium chloride solution, ethyl acetate is used for extracting and then is dried by anhydrous sodium sulfate, the filtrate is used for removing the solvent by a rotary evaporator to obtain residue, the residue is eluted by silica gel column by eluent prepared by petroleum ether and ethyl acetate according to the volume ratio of 30:1, the effluent is collected according to the actual gradient, the effluent containing the target product is combined by TLC detection, the combined effluent is rotated by the rotary evaporator to remove the solvent, and vacuum drying is carried out to obtain 38.2 mg of 1, 2-bis (3- (4-bromophenyl) -5-phenylisothiazol-4-yl) dithioane as yellow solid with the yield of 55%.1H NMR(400MHz,CDCl3)δ7.52-7.36(m,14H),7.18-7.16(m,4H)；13C{1H}NMR(125MHz,CDCl3)δ172.3,169.1,133.7,131.4,130.5,129.91,129.88,129.0,128.9,123.8,122.7。
The specific embodiment eighteen: 60.6 mg (0.2mmol) of 3-phenyl-1- (4- (trifluoromethyl) phenyl) propyl-2-yn-1-one oxime, 102.4 mg (0.4mmol) of elemental sulphur, 91.2 mg (0.6mmol) of 1, 8-diazabicycloundec-7-ene (DBU) are added to 2mL of the solvent NMP-H2O (5:1, V: V). The reaction was stirred at 120 ℃ for 12 hours. After the reaction is finished, cooling is carried out, the reaction solution is filtered to obtain filtrate, the filtrate is washed by saturated sodium chloride solution, ethyl acetate is used for extraction, then anhydrous sodium sulfate is used for drying, the filtrate is used for removing the solvent by a rotary evaporator to obtain a residue, the residue is eluted by silica gel column through eluent prepared by petroleum ether and ethyl acetate according to the volume ratio of 30:1, the effluent is collected according to the actual gradient, the effluent containing the target product is combined by TLC detection, the combined effluent is rotated by the rotary evaporator to remove the solvent, and vacuum drying is carried out to obtain 36.3 mg of 1, 2-bis (5-phenyl-3- (4- (trifluoromethyl) phenyl) isothiazol-4-yl) dithioane as yellow solid, wherein the yield is 54%.1H NMR(400MHz,CDCl3)δ7.66-7.64(m,4H),7.60-7.58(m,4H),7.52-7.48(m,2H),7.45-7.41(m,4H),7.19-7.17(m,4H)；13C{1H}NMR(125MHz,CDCl3)δ172.7,168.8,138.0,131.1(q,JC-F＝32.5Hz),130.1,129.7,129.3,129.00,128.97,125.1,124.2(q,JC-F＝270.0Hz),122.8。
The specific examples are nineteen: 57.0 mg (0.2mmol)1 (naphthalen-2-yl) -3-phenyl-2-yn-1-one oxime, 102.4 mg (0.4mmol) elemental sulfur, 91.2 mg (0.6mmol)1, 8-diazabicycloundec-7-ene (DBU) were added to 2mL solvent NMP-H2O (5:1, V: V). The reaction was stirred at 120 ℃ for 12 hours. After the reaction is finished, cooling is carried out, the reaction solution is filtered to obtain filtrate, the filtrate is washed by saturated sodium chloride solution, ethyl acetate is used for extraction, then anhydrous sodium sulfate is used for drying, the filtrate is used for removing the solvent by a rotary evaporator to obtain residue, the residue is eluted by silica gel column through eluent prepared by petroleum ether and ethyl acetate according to the volume ratio of 30:1, effluent liquid is collected according to actual gradient, TLC detection is carried out, effluent liquid containing a target product is combined, the combined effluent liquid is used for removing the solvent by the rotary evaporator in a rotating mode, vacuum drying is carried out to obtain yellow solid 1, 2-bis (3- (naphthalene-2-yl) -5-phenylisothiazole-4-yl) dithioane 45.2 mg, and the yield is 71%.1H NMR(400MHz,CDCl3)δ7.93-7.82(m,8H),7.60-7.40(m,12H),7.16(d,J＝7.2Hz,4H)；13C{1H}NMR(125MHz,CDCl3)δ172.1,170.4,133.5,133.0,132.3,130.1,129.7,129.1,128.92,128.86,128.8,127.8,127.7,126.9,126.4,126.3,123.2.HRMS(ESI)Calcd for C38H25N2S4 +([M+H]+)637.0895,found 637.0891。
The specific embodiment twenty: 48.2 mg (0.2mmol) of (Z) -3-phenyl-1- (thiophen-2-yl) propyl-2-yn-1 one-O-methyloxime, 102.4 mg (0.4mmol) of elemental sulfur, 91.2 mg (0.6mmol) of 1, 8-diazabicycloundec-7-ene (DBU) are added to 2mL of the solvent NMP-H2O (5:1, V: V). The reaction was stirred at 120 ℃ for 12 hours. Cooling after the reaction, filtering the reaction solution to obtain a filtrate, washing with a saturated sodium chloride solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, removing the solvent from the filtrate with a rotary evaporator to obtain a residue, and passing the residue through a silica gel columnEluting with eluent prepared from petroleum ether and ethyl acetate according to the volume ratio of 30:1, collecting effluent according to actual gradient, detecting by TLC, combining the effluent containing the target product, removing the solvent by rotating the combined effluent by a rotary evaporator, and drying in vacuum to obtain 31.8 mg of 1, 2-bis (5-phenyl-3- (thiophene-2-yl) isothiazol-4-yl) dithiolane as a yellow solid with the yield of 58%.1H NMR(400MHz,CDCl3)δ7.87-7.86(m,2H),7.41-7.35(m,8H),7.23-7.21(m,4H),7.08-7.06(m,2H)；13C{1H}NMR(125MHz,CDCl3)δ173.0,163.4,137.5,129.8,129.7,129.0,128.7,128.0,127.8,127.4,121.7.HRMS(ESI)Calcd for C26H17N2S6 +([M+H]+)548.9710,found 548.9718。
The specific embodiment twenty one: 48.2 mg (0.2mmol) of 1-cyclohexyl-3-phenylprop-2-yn-1-one o-methyloxime, 102.4 mg (0.4mmol) of elemental sulfur, 91.2 mg (0.6mmol) of 1, 8-diazabicycloundec-7-ene (DBU) are added to 2mL of the solvent NMP-H2O (5:1, V: V). The reaction was stirred at 120 ℃ for 12 hours. After the reaction is finished, cooling is carried out, the reaction solution is filtered to obtain filtrate, the filtrate is washed by saturated sodium chloride solution, ethyl acetate is used for extracting and then is dried by anhydrous sodium sulfate, the filtrate is used for removing the solvent by a rotary evaporator to obtain a residue, the residue is eluted by silica gel column by eluent prepared by petroleum ether and ethyl acetate according to the volume ratio of 30:1, the effluent is collected according to the actual gradient, the effluent containing the target product is combined by TLC detection, the combined effluent is rotated by the rotary evaporator to remove the solvent, and vacuum drying is carried out to obtain 29.0 mg of 1, 2-bis (3-cyclohexyl-5-phenylisothiazol-4-yl) disulfane as yellow solid with the yield of 53%.1H NMR(400MHz,CDCl3)δ7.40-7.32(m,6H),7.22-7.21(m,4H),2.89-2.82(m,2H),1.82-1.80(m,8H),1.74-1.73(m,2H),1.57-1.49(m,4H),1.36-1.27(m,6H)；13C{1H}NMR(125MHz,CDCl3)δ178.2,170.9,130.3,129.6,128.9,128.8,123.2,41.1,32.3,26.6,26.2.HRMS(ESI)Calcd for C30H33N2S4 +([M+H]+)549.1521,found 549.1515。
The specific embodiment twenty two: will be 47.0Mg (0.2mmol) of 1, 3-diphenylprop-2-yn-1-one o-methyloxime, 76.8 mg (0.3mmol) of elemental sulfur, 91.2 mg (0.6mmol) of 1, 8-diazabicycloundec-7-ene (DBU) are added to 2mL of the solvent NMP-H2O (5:1, V: V). The reaction was stirred at 120 ℃ for 12 hours. After the reaction is finished, cooling is carried out, the reaction liquid is filtered to obtain filtrate, the filtrate is washed by saturated sodium chloride solution, ethyl acetate is used for extraction, then anhydrous sodium sulfate is used for drying, the filtrate is used for removing the solvent by a rotary evaporator to obtain a residue, the residue is eluted by silica gel column through eluent prepared by petroleum ether and ethyl acetate according to the volume ratio of 30:1, effluent liquid is collected according to actual gradient, TLC detection is carried out, effluent liquid containing a target product is combined, the combined effluent liquid is used for removing the solvent by the rotary evaporator in a rotating mode, vacuum drying is carried out to obtain 27.3 mg of 1, 2-bis (3, 5-diphenyl isothiazole-4-yl) disulfide, and the yield is 51%.
The specific embodiment twenty three: 47.0 mg (0.2mmol) of 1, 3-diphenylprop-2-yn-1-one o-methyloxime, 102.4 mg (0.4mmol) of elemental sulfur, 60.8 mg (0.4mmol) of 1, 8-diazabicycloundec-7-ene (DBU) were added to 2mL of the solvent NMP-H2O (5:1, V: V). The reaction was stirred at 120 ℃ for 12 hours. After the reaction is finished, cooling is carried out, the reaction liquid is filtered to obtain filtrate, the filtrate is washed by saturated sodium chloride solution, ethyl acetate is used for extracting, then anhydrous sodium sulfate is used for drying, the filtrate is used for removing the solvent by a rotary evaporator to obtain a residue, the residue is eluted by silica gel column through eluent prepared by petroleum ether and ethyl acetate according to the volume ratio of 30:1, effluent liquid is collected according to actual gradient, TLC detection is carried out, effluent liquid containing a target product is combined, the combined effluent liquid is used for removing the solvent by the rotary evaporator in a rotating mode, vacuum drying is carried out to obtain yellow solid, 31.6 mg of 1, 2-bis (3, 5-diphenyl isothiazole-4-yl) disulfide, and the yield is 59%.
The specific embodiment twenty four: 47.0 mg (0.2mmol) of 1, 3-diphenylprop-2-yn-1-one o-methyloxime, 102.4 mg (0.4mmol) of elemental sulfur, 91.2 mg (0.6mmol) of 1, 8-diazabicycloundec-7-ene (DBU) were added to 2mL of the solvent NMP-H2O (5:1, V: V). The reaction was stirred at 100 ℃ for 12 hours. Cooling after the reaction is finished, filtering the reaction solution to obtain filtrate, washing the filtrate by using saturated sodium chloride solution, extracting by using ethyl acetate, and then using anhydrous sulfurDrying sodium salt, removing solvent from the filtrate by using a rotary evaporator to obtain a residue, eluting the residue by using a silica gel column by using an eluent prepared from petroleum ether and ethyl acetate according to the volume ratio of 30:1, collecting the effluent according to an actual gradient, detecting by using TLC (thin layer chromatography), combining the effluent containing the target product, removing the solvent from the combined effluent by using the rotary evaporator in a rotating manner, and drying in vacuum to obtain a yellow solid, 35.3 mg of 1, 2-bis (3, 5-diphenylisothiazol-4-yl) disulfide with the yield of 66%.
In the embodiment of the invention, alkynyl oxime ether is taken as a substrate, elemental sulfur is taken as a sulfur source, 1, 8-diazabicycloundecen-7-ene (DBU) is taken as alkali, and NMP-H2O (5:1, V: V) is used as a solvent, and the reaction is stirred for 12 hours at the temperature of 100-120 ℃. Wherein in examples one to nine, Ar in the alkynyl oxime ether is substituted with different substituents as variables; examples ten to twenty-one are variables where R in alkynyl oxime ethers is substituted with different substituents; example twenty two is variable in the amount of elemental sulfur; example twenty three is a variable of the amount of the base 1, 8-diazabicycloundecen-7-ene (DBU); the twenty-four example is based on the reaction temperature as a variable.
According to the invention, the intermediate product does not need to be separated, the target product can be directly synthesized by simple raw materials, the process is simplified, the energy consumption is low, the waste solution discharge is reduced, the environmental pollution is reduced, and the yield reaches 89% at most; in the above embodiment, alkynyl oxime ethers containing different substituents are selected to react with elemental sulfur, so that a series of isothiazol-4-yl disulfide derivatives can be prepared. The present invention is not limited to the above embodiments, and those skilled in the art can implement the present invention in other embodiments according to the disclosure of the present invention, or make simple changes or modifications on the design structure and idea of the present invention, and fall into the protection scope of the present invention.
Claims (4)
1. A method for synthesizing isothiazol-4-yl disulfide derivatives, comprising the steps of: taking alkynyl oxime ether as a substrate, elemental sulfur as a sulfur source, 1, 8-diazabicycloundecen-7-ene as alkali and NMP-H2Mixing O at a volume ratio of 5:1As a solvent, stirring and reacting for 12 hours at 100-120 ℃, and the chemical reaction formula is as follows:
the-R is one of phenyl, 4-methylphenyl, 2-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 3-chlorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 2-naphthyl, 2-thienyl and cyclohexyl;
and the-Ar is one of phenyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 4-tert-butylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl and 4-trifluoromethylphenyl.
2. The method for synthesizing isothiazol-4-yl disulfide derivatives according to claim 1, wherein: the amount of the elemental sulfur is 2 equivalents of the alkynyl oxime ether.
3. The method for the synthesis of isothiazol-4-yl disulfide derivatives according to claim 1, wherein: the base is used in an amount of 3 equivalents of the alkynyl oxime ether.
4. The method for the synthesis of isothiazol-4-yl disulfide derivatives according to claim 1, wherein: after the reaction is finished, filtering the reaction solution, washing the reaction solution by using a saturated sodium chloride solution, extracting the reaction solution by using ethyl acetate, drying the extraction solution by using anhydrous sodium sulfate, removing the solvent from the filtrate by using a rotary evaporator to obtain a residue, carrying out column layer separation on the residue through a silica gel column, leaching the residue through an eluent, collecting an effluent containing a target product, combining the effluent, and removing the solvent through vacuum concentration to obtain the target product.
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