CN110272450B - Beta-thiocarbonyl diphosphonic acid derivative and preparation method thereof - Google Patents
Beta-thiocarbonyl diphosphonic acid derivative and preparation method thereof Download PDFInfo
- Publication number
- CN110272450B CN110272450B CN201910606595.8A CN201910606595A CN110272450B CN 110272450 B CN110272450 B CN 110272450B CN 201910606595 A CN201910606595 A CN 201910606595A CN 110272450 B CN110272450 B CN 110272450B
- Authority
- CN
- China
- Prior art keywords
- beta
- mmol
- reaction
- derivatives
- raw materials
- 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.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 153
- 239000002994 raw material Substances 0.000 claims abstract description 46
- XLTUPERVRFLGLJ-UHFFFAOYSA-N isothiocyanato(trimethyl)silane Chemical compound C[Si](C)(C)N=C=S XLTUPERVRFLGLJ-UHFFFAOYSA-N 0.000 claims abstract description 35
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims abstract description 29
- 229910052698 phosphorus Inorganic materials 0.000 claims abstract description 29
- 239000011574 phosphorus Substances 0.000 claims abstract description 29
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 24
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical compound CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000003054 catalyst Substances 0.000 claims abstract description 19
- 150000001345 alkine derivatives Chemical class 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 17
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 15
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims abstract description 13
- 229910052802 copper Inorganic materials 0.000 claims abstract description 13
- 239000010949 copper Substances 0.000 claims abstract description 13
- 150000002978 peroxides Chemical class 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 10
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 8
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims abstract description 7
- 239000011701 zinc Substances 0.000 claims abstract description 6
- 229910052725 zinc Inorganic materials 0.000 claims abstract description 6
- 150000008301 phosphite esters Chemical class 0.000 claims abstract description 5
- 238000004440 column chromatography Methods 0.000 claims description 31
- 238000004809 thin layer chromatography Methods 0.000 claims description 29
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- 239000000126 substance Substances 0.000 claims description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical group CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000003999 initiator Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 97
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 65
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 62
- 239000000047 product Substances 0.000 description 59
- 238000005160 1H NMR spectroscopy Methods 0.000 description 31
- 239000012043 crude product Substances 0.000 description 29
- 239000003208 petroleum Substances 0.000 description 29
- 230000015572 biosynthetic process Effects 0.000 description 26
- 238000003786 synthesis reaction Methods 0.000 description 26
- YFPJFKYCVYXDJK-UHFFFAOYSA-N Diphenylphosphine oxide Chemical compound C=1C=CC=CC=1[P+](=O)C1=CC=CC=C1 YFPJFKYCVYXDJK-UHFFFAOYSA-N 0.000 description 23
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 description 18
- -1 diphosphonate compound Chemical class 0.000 description 16
- HYPPXZBJBPSRLK-UHFFFAOYSA-N diphenoxylate Chemical compound C1CC(C(=O)OCC)(C=2C=CC=CC=2)CCN1CCC(C#N)(C=1C=CC=CC=1)C1=CC=CC=C1 HYPPXZBJBPSRLK-UHFFFAOYSA-N 0.000 description 15
- 229960004192 diphenoxylate Drugs 0.000 description 15
- DKGAVHZHDRPRBM-UHFFFAOYSA-N tert-butyl alcohol Substances CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 12
- CQCGPNRIAFVNBY-UHFFFAOYSA-N [ethenyl(phenyl)phosphoryl]benzene Chemical compound C=1C=CC=CC=1P(=O)(C=C)C1=CC=CC=C1 CQCGPNRIAFVNBY-UHFFFAOYSA-N 0.000 description 11
- PDZKZMQQDCHTNF-UHFFFAOYSA-M copper(1+);thiocyanate Chemical compound [Cu+].[S-]C#N PDZKZMQQDCHTNF-UHFFFAOYSA-M 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 6
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 5
- 125000002252 acyl group Chemical group 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- LTLVZQZDXQWLHU-UHFFFAOYSA-N 1-bromo-4-ethynylbenzene Chemical group BrC1=CC=C(C#C)C=C1 LTLVZQZDXQWLHU-UHFFFAOYSA-N 0.000 description 3
- DGLHLIWXYSGYBI-UHFFFAOYSA-N 1-chloro-2-ethynylbenzene Chemical group ClC1=CC=CC=C1C#C DGLHLIWXYSGYBI-UHFFFAOYSA-N 0.000 description 3
- ZASXCTCNZKFDTP-UHFFFAOYSA-N 1-ethynyl-3-methoxybenzene Chemical group COC1=CC=CC(C#C)=C1 ZASXCTCNZKFDTP-UHFFFAOYSA-N 0.000 description 3
- RENYIDZOAFFNHC-UHFFFAOYSA-N 1-ethynyl-3-methylbenzene Chemical group CC1=CC=CC(C#C)=C1 RENYIDZOAFFNHC-UHFFFAOYSA-N 0.000 description 3
- KBIAVTUACPKPFJ-UHFFFAOYSA-N 1-ethynyl-4-methoxybenzene Chemical group COC1=CC=C(C#C)C=C1 KBIAVTUACPKPFJ-UHFFFAOYSA-N 0.000 description 3
- GAZZTEJDUGESGQ-UHFFFAOYSA-N 1-ethynyl-4-nitrobenzene Chemical group [O-][N+](=O)C1=CC=C(C#C)C=C1 GAZZTEJDUGESGQ-UHFFFAOYSA-N 0.000 description 3
- LWISLHRIEATKTM-UHFFFAOYSA-N 2-Ethynylthiophene Chemical compound C#CC1=CC=CS1 LWISLHRIEATKTM-UHFFFAOYSA-N 0.000 description 3
- ULLYOKZYOHMTIJ-UHFFFAOYSA-N 2-ethynyl-n-methylaniline Chemical group CNC1=CC=CC=C1C#C ULLYOKZYOHMTIJ-UHFFFAOYSA-N 0.000 description 3
- NHUBNHMFXQNNMV-UHFFFAOYSA-N 2-ethynylpyridine Chemical compound C#CC1=CC=CC=N1 NHUBNHMFXQNNMV-UHFFFAOYSA-N 0.000 description 3
- KSZVOXHGCKKOLL-UHFFFAOYSA-N 4-Ethynyltoluene Chemical group CC1=CC=C(C#C)C=C1 KSZVOXHGCKKOLL-UHFFFAOYSA-N 0.000 description 3
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 3
- 229910021592 Copper(II) chloride Inorganic materials 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- JRXXLCKWQFKACW-UHFFFAOYSA-N biphenylacetylene Chemical compound C1=CC=CC=C1C#CC1=CC=CC=C1 JRXXLCKWQFKACW-UHFFFAOYSA-N 0.000 description 3
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 3
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 3
- CZHYKKAKFWLGJO-UHFFFAOYSA-N dimethyl phosphite Chemical compound COP([O-])OC CZHYKKAKFWLGJO-UHFFFAOYSA-N 0.000 description 3
- NPTDXPDGUHAFKC-UHFFFAOYSA-N ethynylcyclopropane Chemical group C#CC1CC1 NPTDXPDGUHAFKC-UHFFFAOYSA-N 0.000 description 3
- YVXHZKKCZYLQOP-UHFFFAOYSA-N hept-1-yne Chemical compound CCCCCC#C YVXHZKKCZYLQOP-UHFFFAOYSA-N 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- GRBJPHPMYOUMJV-UHFFFAOYSA-N 1-chloro-3-ethynylbenzene Chemical group ClC1=CC=CC(C#C)=C1 GRBJPHPMYOUMJV-UHFFFAOYSA-N 0.000 description 2
- LFZJRTMTKGYJRS-UHFFFAOYSA-N 1-chloro-4-ethynylbenzene Chemical group ClC1=CC=C(C#C)C=C1 LFZJRTMTKGYJRS-UHFFFAOYSA-N 0.000 description 2
- QXSWHQGIEKUBAS-UHFFFAOYSA-N 1-ethynyl-4-fluorobenzene Chemical group FC1=CC=C(C#C)C=C1 QXSWHQGIEKUBAS-UHFFFAOYSA-N 0.000 description 2
- HRDCVMSNCBAMAM-UHFFFAOYSA-N 3-prop-2-ynoxyprop-1-yne Chemical compound C#CCOCC#C HRDCVMSNCBAMAM-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 206010036030 Polyarthritis Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- QDEOKXOYHYUKMS-UHFFFAOYSA-N but-3-ynylbenzene Chemical compound C#CCCC1=CC=CC=C1 QDEOKXOYHYUKMS-UHFFFAOYSA-N 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 2
- BNKAXGCRDYRABM-UHFFFAOYSA-N ethenyl dihydrogen phosphate Chemical compound OP(O)(=O)OC=C BNKAXGCRDYRABM-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- JYJVVHFRSFVEJM-UHFFFAOYSA-N iodosobenzene Chemical compound O=IC1=CC=CC=C1 JYJVVHFRSFVEJM-UHFFFAOYSA-N 0.000 description 2
- JPGRSTBIEYGVNO-UHFFFAOYSA-N methyl 4-ethynylbenzoate Chemical compound COC(=O)C1=CC=C(C#C)C=C1 JPGRSTBIEYGVNO-UHFFFAOYSA-N 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- KOSORCNALVBYBP-UHFFFAOYSA-N pent-4-ynylbenzene Chemical compound C#CCCCC1=CC=CC=C1 KOSORCNALVBYBP-UHFFFAOYSA-N 0.000 description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 2
- 208000030428 polyarticular arthritis Diseases 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 2
- WILMTQKUPOOLFE-UHFFFAOYSA-N 1-methoxy-4-(4-methoxyphenyl)phosphonoylbenzene Chemical compound C1=CC(OC)=CC=C1P(=O)C1=CC=C(OC)C=C1 WILMTQKUPOOLFE-UHFFFAOYSA-N 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 1
- DQQNMIPXXNPGCV-UHFFFAOYSA-N 3-hexyne Chemical compound CCC#CCC DQQNMIPXXNPGCV-UHFFFAOYSA-N 0.000 description 1
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 1
- YACFFSVYSPMSGS-UHFFFAOYSA-N 3-methoxyprop-1-yne Chemical compound COCC#C YACFFSVYSPMSGS-UHFFFAOYSA-N 0.000 description 1
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- UPEUQDJSUFHFQP-UHFFFAOYSA-N 4-phenylbut-3-yn-2-one Chemical compound CC(=O)C#CC1=CC=CC=C1 UPEUQDJSUFHFQP-UHFFFAOYSA-N 0.000 description 1
- 229940122361 Bisphosphonate Drugs 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- OCBFRERDBGGMOA-UHFFFAOYSA-N C(=C)P(C1=CC=C(C=C1)OC)(C1=CC=C(C=C1)OC)=O Chemical compound C(=C)P(C1=CC=C(C=C1)OC)(C1=CC=C(C=C1)OC)=O OCBFRERDBGGMOA-UHFFFAOYSA-N 0.000 description 1
- IJQKEPDGLYUCMI-UHFFFAOYSA-N C=1C=C(C#N)C=CC=1P(=O)C1=CC=C(C#N)C=C1 Chemical compound C=1C=C(C#N)C=CC=1P(=O)C1=CC=C(C#N)C=C1 IJQKEPDGLYUCMI-UHFFFAOYSA-N 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 229910021590 Copper(II) bromide Inorganic materials 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- 102000003960 Ligases Human genes 0.000 description 1
- 108090000364 Ligases Proteins 0.000 description 1
- FKRMBNBVCHDJQL-UHFFFAOYSA-N N#CSC(C1=CC=CC=C1)=C(C1=CC=CC=C1)P(C1=CC=CC=C1)(C1=CC=CC=C1)=O Chemical compound N#CSC(C1=CC=CC=C1)=C(C1=CC=CC=C1)P(C1=CC=CC=C1)(C1=CC=CC=C1)=O FKRMBNBVCHDJQL-UHFFFAOYSA-N 0.000 description 1
- IKGLXUBVELOTFD-UHFFFAOYSA-N N#CSC(C1=CC=CC=C1)=CP(C1=CC=CC=C1)(C1=CC=CC=C1)=O Chemical compound N#CSC(C1=CC=CC=C1)=CP(C1=CC=CC=C1)(C1=CC=CC=C1)=O IKGLXUBVELOTFD-UHFFFAOYSA-N 0.000 description 1
- HSZXWHSZMVDOMT-UHFFFAOYSA-N N#CSC(C1CC1)=CP(C1=CC=CC=C1)(C1=CC=CC=C1)=O Chemical compound N#CSC(C1CC1)=CP(C1=CC=CC=C1)(C1=CC=CC=C1)=O HSZXWHSZMVDOMT-UHFFFAOYSA-N 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- CRFJRGSTIQFTQW-UHFFFAOYSA-N acetylene fluorobenzene Chemical group C#C.FC1=CC=CC=C1 CRFJRGSTIQFTQW-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- ILLHQJIJCRNRCJ-UHFFFAOYSA-N dec-1-yne Chemical compound CCCCCCCCC#C ILLHQJIJCRNRCJ-UHFFFAOYSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- AJVBXLXLODZUME-UHFFFAOYSA-N ethenyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=C)C1=CC=CC=C1 AJVBXLXLODZUME-UHFFFAOYSA-N 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000002540 isothiocyanates Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 150000003003 phosphines Chemical class 0.000 description 1
- 125000005543 phthalimide group Chemical group 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000005031 thiocyano group Chemical group S(C#N)* 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
- C07F9/32—Esters thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4071—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4075—Esters with hydroxyalkyl compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
- C07F9/5304—Acyclic saturated phosphine oxides or thioxides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
- C07F9/5316—Unsaturated acyclic phosphine oxides or thioxides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
- C07F9/5325—Aromatic phosphine oxides or thioxides (P-C aromatic linkage)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/572—Five-membered rings
- C07F9/5728—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/58—Pyridine rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms
- C07F9/655345—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a five-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
- C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
- C07F9/65842—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring
- C07F9/65846—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring the phosphorus atom being part of a six-membered ring which may be condensed with another ring system
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a beta-thiocarbonyl diphosphonic acid derivative and a preparation method thereof, wherein the preparation method comprises the following steps: dissolving alkyne, phosphorus reagent, trimethylsilyl isothiocyanate, a copper catalyst and peroxide in a solvent, and reacting at 30-70 ℃ to obtain a beta-thiocyanato alkenyl phosphono derivative; then, preparing the beta-thiocarbonylphosphinyl derivatives by taking the beta-thiocyanoalkenylphosphono derivatives as raw materials in the presence of a zinc catalyst and acetic acid; then, the beta-thiophosphoryl carbonyl derivatives are used as raw materials to prepare the beta-thiophosphoryl carbonyl diphosphonate derivatives in the presence of phosphite ester, cuprous trifluoromethanesulfonate and di-tert-butyl peroxide. The method uses alkyne as an initiator, has the advantages of easily obtained raw materials, wide variety, simple steps, mild reaction conditions, high yield of target products, little pollution and simple reaction operation and post-treatment process, and is suitable for industrial production.
Description
The invention belongs to a beta-thiocyano alkenyl phosphono derivative and a preparation method thereof, and a divisional application of the invention with application date of 2017, 9 and 8 and application number of 201710808044.0, and belongs to the part of the preparation method of the derivative.
Technical Field
The invention belongs to the technical field of preparation of organic compounds, and particularly relates to a beta-thiocarbonyl diphosphonic acid derivative and a preparation method thereof.
Background
The organic phosphine medicine has important application value in the fields of treating cancer, diminishing inflammation, resisting osteoporosis and the like; the organic phosphine synthetase is an important anticancer drug, and can accelerate the apoptosis of tumor cells so as to play a role in resisting cancer. In addition, the organic phosphine compounds also have an anti-inflammatory effect and have good therapeutic effects on polyarthritis (Kamel, A., Geronikaki, A., Abdou, W.M. Inhibitory effect of novel S,N-bisphosphonates on some carcinoma cell lines, osteoarthritis, and chronic inflammation. Eur. J. Med. Chem. 2012, 51, 239.)。
W.M. Abdou et al disclose a synthetic method of a diphosphonate compound containing S, N, and test the anticancer and anti-inflammatory activity of the compound, the in vitro test result shows that the compound shows obvious anticancer activity to tested breast cancer cells, cervical cancer cells, liver cancer cells and colon cancer cells; in addition, the compounds have good anti-inflammatory activity on polyarthritis, and particularly, the compounds do not show obvious toxicity on normal cells and have good application prospect. The method takes benzothiazine-2, 4-dithione as raw material, and the benzothiazine-2, 4-dithione is processed by diphosphoryl methylation and CS removal2Cyclization and the like to obtain a compound; the raw materials are difficult to obtain, the route is long, the reaction conditions are harsh, the selectivity is avoided, and in the reaction, the toxic liquid CS is released2It is very volatile and has foul smell, and can invade human body through respiratory tract and skin to damage nervous system and blood vessel, resulting in cardiovascular disease. Therefore, it is very important to develop a synthesis method with mild reaction conditions, wide application range, simple reaction steps and simple and easily-obtained raw materials.
Disclosure of Invention
The invention aims to provide a method for preparing beta-thiocyano alkenyl phosphono derivatives and related derivative products, which has the advantages of simple raw material source, mild reaction conditions, simple post-treatment, high yield and the like.
In order to achieve the purpose of the invention, the technical scheme adopted by the invention is as follows: a process for the preparation of β -thiocyanoalkenylphosphono derivatives comprising the steps of: dissolving alkyne, phosphorus reagent, trimethylsilyl isothiocyanate, a copper catalyst and peroxide in a solvent, and reacting at 30-70 ℃ to obtain the beta-thiocyano alkenyl phosphono derivative.
The invention also discloses a preparation method of the beta-thiocarbonylphosphinyl derivative, which comprises the following steps: dissolving alkyne, phosphorus reagent, trimethylsilyl isothiocyanate, a copper catalyst and peroxide in a solvent, and reacting at 30-70 ℃ to obtain a beta-thiocyanato alkenyl phosphono derivative; then the beta-thiocyano alkenyl phosphonic derivative is used as a raw material, and the beta-thiocyano phosphonic derivative is prepared in the presence of a zinc catalyst and acetic acid.
The invention also discloses a preparation method of the beta-thiocarbonyl diphosphonic acid derivative, which comprises the following steps: dissolving alkyne, phosphorus reagent, trimethylsilyl isothiocyanate, a copper catalyst and peroxide in a solvent, and reacting at 30-70 ℃ to obtain a beta-thiocyanato alkenyl phosphono derivative; then, preparing the beta-thiocarbonylphosphinyl derivatives by taking the beta-thiocyanoalkenylphosphono derivatives as raw materials in the presence of a zinc catalyst and acetic acid; then, the beta-thiophosphoryl carbonyl derivatives are used as raw materials to prepare the beta-thiophosphoryl carbonyl diphosphonate derivatives in the presence of phosphite ester, cuprous trifluoromethanesulfonate and di-tert-butyl peroxide.
The invention also discloses a preparation method of the beta-mercapto azaphospho heterocyclic derivative, which comprises the following steps: dissolving alkyne, phosphorus reagent, trimethylsilyl isothiocyanate, a copper catalyst and peroxide in a solvent, and reacting at 30-70 ℃ to obtain a beta-thiocyanato alkenyl phosphono derivative; then, preparing the beta-thiocarbonylphosphinyl derivatives by taking the beta-thiocyanoalkenylphosphono derivatives as raw materials in the presence of a zinc catalyst and acetic acid; then, preparing the beta-thiophosphoryl diphosphonate derivatives from the beta-thiophosphoryl phosphonyl derivatives serving as raw materials in the presence of phosphite ester, cuprous trifluoromethanesulfonate and di-tert-butyl peroxide; and finally, preparing the beta-mercapto azaphospho heterocyclic derivative by taking the beta-thiocarbonyl diphosphonic acyl derivative as a raw material in the presence of sodium ethoxide and hydrochloric acid.
The invention also discloses a preparation method of the beta-thioindolone derivative, which comprises the following steps: dissolving alkyne, phosphorus reagent, trimethylsilyl isothiocyanate, a copper catalyst and peroxide in a solvent, and reacting at 30-70 ℃ to obtain a beta-thiocyanato alkenyl phosphono derivative; then, preparing the beta-thiocarbonylphosphinyl derivatives by taking the beta-thiocyanoalkenylphosphono derivatives as raw materials in the presence of a zinc catalyst and acetic acid; then, preparing the beta-thiophosphoryl diphosphonate derivatives from the beta-thiophosphoryl phosphonyl derivatives serving as raw materials in the presence of phosphite ester, cuprous trifluoromethanesulfonate and di-tert-butyl peroxide; and finally, preparing the beta-thioindolone derivatives by taking the beta-thiocarbonyl diphosphonic acyl derivatives as raw materials in the presence of iodosobenzene and tetra-n-butyl amine iodide.
The invention also discloses the application of alkyne, phosphorus reagent and trimethylsilyl isothiocyanate as raw materials in preparing the beta-thiocyano alkenyl phosphonic derivatives; or the application of copper catalyst and peroxide as additives in the preparation of beta-thiocyano alkenyl phosphono derivatives.
In the application, alkyne, phosphorus reagent, trimethylsilyl isothiocyanate, a copper catalyst and peroxide are dissolved in a solvent and react at the temperature of 30-70 ℃ to obtain the beta-thiocyanato alkenyl phosphonic acyl derivative.
In the invention, the chemical structural formula of the alkyne is one of the following chemical structures:
wherein R is selected from one of alkyl, N-alkyl phthalimide group, aryl alkyl and ethyl acetate group; x is H orWherein R is2One selected from alkyl and alkoxy; ar is selected from one of the following chemical structures:
wherein R is1One selected from alkyl, alkoxy, halogen, nitro, cyano and ester group; y is selected from O, S, N; r3Is selected from one of alkyl, alkoxy and halogen.
The phosphorus reagent of the invention is shown as the following structural general formula:
wherein R is4Selected from alkoxy or aryl.
The chemical formula of the copper catalyst is CuXnWherein X is one of Cl, Br, I or SCN; n is 1 or 2;
the beta-thiocyano alkenyl phosphono derivative is shown as the following chemical structural general formula:
the beta-thiophosphoryl carbonyl derivatives of the invention are shown as the following chemical structural general formula:
the beta-thiocarbonyl diphosphonic acyl derivative is shown as the following chemical structural general formula:
the beta-mercapto azaphospho heterocyclic derivative is shown as the following chemical structural formula:
the beta-thioindolone derivatives are shown as the following chemical structural formula:
the solvent is selected from one of ethanol, acetonitrile, tetrahydrofuran, acetone, toluene, N-dimethylformamide or N-methylpyrrolidone.
The alkynes of the present invention may have the following chemical structural formula:
preferably, the alkyne is selected from the group consisting of phenylacetylene, 2-methylaminophenylacetylene, 4-methylphenylacetylene, 4-methoxyphenylacetylene, 4-fluorophenylacetylene, 4-chlorophenylacetylene, 4-bromophenylacetylene, 4-nitrophenylacetylene, methyl 4-ethynylbenzoate, 3-methylphenylacetylene, 3-methoxyphenylacetylene, 3-chlorophenylacetylene, 2-chlorophenylacetylene, tolane, 2-ethynylthiophene, 2-ethynylpyridine, 4-phenylbutyne, 5-phenylpentyne, 1-phenylbutynin-3-one, 2-cyclopropylacetylene, n-hept-1-yne, n-nony-1-yne, n-decan-1-yne, hex-3-yne, methylpropargyl ether, propargyl ether, One of bis (propargyl) ether and trimethylsilyl acetylene; the phosphorus reagent is selected from one of dimethyl phosphite, diethyl phosphite, diphenyl phosphine oxide, di (4-methoxyphenyl) phosphine oxide or di (4-cyanophenyl) phosphine oxide.
In the above technical scheme, the reaction is followed by Thin Layer Chromatography (TLC) until complete completion.
In the technical scheme, the ratio of alkyne, phosphorus reagent, trimethylsilyl isothiocyanate, copper catalyst and peroxide is 1: 1-3: 0.1-0.3: 1-3 by mol.
In the technical scheme, after the reaction is finished, the product is subjected to column chromatography separation and purification treatment.
The reaction process of the above technical scheme can be expressed as follows:
due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:
1. the invention uses alkyne derivatives as the starting materials, and has the advantages of easily available raw materials, low toxicity, low cost and various types.
2. The invention has wide application range, is not only suitable for aryl alkyne, but also suitable for common alkyl alkyne.
3. The thiocyano reagent used in the invention is easy to obtain and low in cost.
4. The method disclosed by the invention has the advantages of mild reaction conditions, short reaction time, high yield of target products, simple reaction operation and post-treatment process, and suitability for industrial production.
Detailed Description
The invention is further described below with reference to the following examples:
the first embodiment is as follows: synthesis of (2-phenyl-2-thiocyano) ethenyl diphenylphosphine oxide
The method takes phenylacetylene and diphenyl phosphine oxide as raw materials, and comprises the following reaction steps:
adding phenylacetylene (0.041 g, 0.4 mmol), phosphorus diphenoxylate (0.081 g, 0.4 mmol), trimethylsilyl isothiocyanate (0.052 g, 0.4 mmol), CuCl (0.04g, 0.04 mmol), tert-butyl peroxide (0.051 g, 0.4 mmol) and ethanol (3 mL) into a reaction bottle, and reacting at 70 ℃;
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 84%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 7.85 – 7.71 (m, 4H), 7.67 – 7.39 (m, 11H), 6.62 (d, J = 19.1 Hz, 1H)。
example two: synthesis of (2- (4-tolyl) -2-thiocyano)) vinyldiphenylphosphine oxide
4-methyl phenylacetylene and diphenyl phosphine oxide are used as raw materials, and the reaction steps are as follows:
4-Methylphenylacetylene (0.046 g, 0.4 mmol), diphenoxy ether were charged in a reaction flaskPhosphorus (0.162 g, 0.8 mmol), trimethylsilyl isothiocyanate (0.104 g, 0.8 mmol), CuCl (0.08g, 0.08 mmol), t-butanol peroxide (0.102 g, 0.8 mmol) and acetonitrile (3 mL), at 60 ℃;
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 86%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 7.81 – 7.71 (m, 4H), 7.61 – 7.49 (m, 6H), 7.44 – 7.40 (d, J = 8.1 Hz, 2H), 7.24 (s, 2H), 6.60 (d, J = 19.1 Hz, 1H), 2.39 (s, 3H)。
example three: synthesis of (2- (3-tolyl) -2-thiocyano)) vinyldiphenylphosphine oxide
3-methyl phenylacetylene and diphenyl phosphine oxide are used as raw materials, and the reaction steps are as follows:
3-methylphenylacetylene (0.046 g, 0.4 mmol), phosphorus diphenoxylate (0.243 g, 1.2 mmol), trimethylsilyl isothiocyanate (0.154 g, 1.2 mmol), CuCl (0.12g, 0.12 mmol), tert-butyl peroxide (0.154 g, 1.2 mmol) and acetone (3 mL) were added to a reaction flask and reacted at 50 ℃;
the crude product obtained after the reaction is separated by column chromatography (Ethyl acetate: petroleum ether = 1:1), yielding the desired product (89% yield). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 7.88 – 7.79 (m, 4H), 7.66 – 7.54 (m, 6H), 7.48 – 7.30 (m, 3H), 7.24 (d, J = 19.0 Hz,1H), 2.37 (s, 3H)。
example four: synthesis of (2- (3-methoxyphenyl) -2-thiocyano)) vinyldiphenylphosphine oxide
3-methoxy phenylacetylene and diphenyl phosphine oxide are used as raw materials, and the reaction steps are as follows:
adding 3-methoxyphenylacetylene (0.053 g, 0.4 mmol), phosphorus diphenoxylate (0.081 g, 0.4 mmol), trimethylsilyl isothiocyanate (0.052 g, 0.4 mmol), CuBr (0.056g, 0.04 mmol), tert-butyl peroxide (0.154 g, 1.2 mmol) and tetrahydrofuran (3 mL) into a reaction flask, and reacting at 40 ℃;
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 83%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 7.73 – 7.70 (m, 4H), 7.62 – 7.47 (m, 6H), 7.39 – 7.33 (m, 1H), 7.10 (d, J = 7.7 Hz, 1H), 7.05 – 6.95 (m, 2H), 6.63 (d, J = 19.2 Hz, 1H), 3.85 (s, 3H)。
example five: synthesis of (2- (4-methoxyphenyl) -2-thiocyano)) vinyldiphenylphosphine oxide
4-methoxy phenylacetylene and diphenyl phosphine oxide are used as raw materials, and the reaction steps are as follows:
4-methoxyphenylacetylene (0.053 g, 0.4 mmol), diphenylphosphine (0.081 g, 0.4 mmol), trimethylsilyl isothiocyanate (0.052 g, 0.4 mmol), CuBr (0.112g, 0.08 mmol), tert-butyl peroxide (0.154 g, 1.2 mmol) and toluene (3 mL) were charged in a reaction flask and reacted at 30 ℃;
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 91%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 7.8 – 7.72 (m, 4H), 7.60 – 7.48 (m, 8H), 6.95 (d, J = 8.8 Hz, 2H), 6.58 (d, J = 18.9 Hz, 2H), 3.85 (s, 3H)。
example six: synthesis of (2- (2-chlorophenyl) -2-thiocyano)) vinyldiphenylphosphine oxide
2-chloro phenylacetylene and diphenyl phosphine oxide are used as raw materials, and the reaction steps are as follows:
2-chlorophenylacetylene (0.054 g, 0.4 mmol), phosphorus diphenoxylate (0.081 g, 0.4 mmol), trimethylsilyl isothiocyanate (0.052 g, 0.4 mmol), CuBr (0.056g, 0.04 mmol), tert-butyl peroxide (0.154 g, 1.2 mmol) and N, N-dimethylformamide (3 mL) are added into a reaction bottle, and reaction is carried out at 50 ℃;
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 82%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 7.81 – 7.70 (m, 4H), 7.62 – 7.56(m, 2H), 7.55 – 7.48 (m, 5H), 7.41 – 7.34 (m, 3H), 6.49 (d, J= 19.8 Hz, 1H)。
example seven: synthesis of (2- (3-chlorophenyl) -2-thiocyano)) vinyldiphenylphosphine oxide
3-chloro phenylacetylene and diphenyl phosphine oxide are used as raw materials, and the reaction steps are as follows:
3-Chlorobenzeneacetylene (0.054 g, 0.4 mmol), phosphorus diphenoxylate (0.162 g, 0.8 mmol), trimethylsilyl isothiocyanate (0.104 g, 0.8 mmol), CuI (0.076g, 0.04 mmol), tert-butanol peroxide (0.154 g, 1.2 mmol) and N-methylpyrrolidone (3 mL) were charged into a reaction flask and reacted at 50 ℃;
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 80%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 7.90 – 7.79 (m, 4H), 7.77 (s, 1H), 7.66 – 7.52 (m, 9H), 7.38 (d, J = 18.6 Hz, 1H)。
example eight: synthesis of (2- (4-chlorophenyl) -2-thiocyano)) vinyldiphenylphosphine oxide
4-chloro phenylacetylene and diphenyl phosphine oxide are used as raw materials, and the reaction steps are as follows:
4-Chlorobenzeneacetylene (0.054 g, 0.4 mmol), phosphorus diphenoxylate (0.162 g, 0.8 mmol), trimethylsilyl isothiocyanate (0.104 g, 0.8 mmol), CuI (0.152g, 0.08 mmol), tert-butyl peroxide (0.154 g, 1.2 mmol) and N-methylpyrrolidone (3 mL) were charged into a reaction flask and reacted at 60 ℃;
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 85%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 7.79 – 7.71 (m, 4.3H), 7.66 – 7.56 (m, 4.3H), 7.55 – 7.49 (m,4.3H), 7.48 – 7.42 (m, 4.3H), 7.39 (dd, J = 7.6, 2.8 Hz, 1.45H), 7.30 (d, J = 8.4 Hz, 0.8H), 7.16 (d, J = 8.3 Hz, 0.8H), 7.01 (d, J = 13.6 Hz, 0.4H), 6.62 (d, J = 18.8 Hz, 1H)。
example nine: synthesis of (2- (4-fluorophenyl) -2-thiocyano)) vinyldiphenylphosphine oxide
4-fluorobenzene acetylene and diphenyl phosphine oxide are used as raw materials, and the reaction steps are as follows:
4-Fluorophenylacetylene (0.048 g, 0.4 mmol), phosphorus diphenoxylate (0.162 g, 0.8 mmol), trimethylsilyl isothiocyanate (0.104 g, 0.8 mmol), CuI (0.076g, 0.04 mmol), tert-butyl peroxide (0.154 g, 1.2 mmol) and acetonitrile (3 mL) are added into a reaction flask and reacted at 70 ℃;
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 75%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 7.82 – 7.71 (m, 4H), 7.64 – 7.45 (m, 8H), 7.19 – 7.07 (m, 2H), 6.60 (d, J = 18.9 Hz, 1H)。
example ten: synthesis of (2- (4-bromophenyl) -2-thiocyano)) vinyldiphenylphosphine
4-bromophenylacetylene and diphenyl phosphine oxide are used as raw materials, and the reaction steps are as follows:
a reaction flask was charged with 4-bromophenylacetylene (0.072 g, 0.4 mmol), phosphorus diphenoxylate (0.081 g, 0.4 mmol), trimethylsilyl isothiocyanate (0.052 g, 0.4 mmol), CuCl2(0.056g, 0.04 mmol), t-butanol peroxide (0.154 g, 1.2 mmol) and acetonitrile (3 mL), at 50 ℃;
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 72%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 7.89 – 7.69 (m, 5H), 7.66 – 7.30 (m, 16.7H), 7.24 – 7.14 (m, 1.6H), 7.01 (d, J = 13.6 Hz, 0.7H) 6.62 (d, J = 18.8 Hz, 1H)。
example eleven: synthesis of (2- (4-nitrophenyl) -2-thiocyano)) vinyldiphenylphosphine oxide
4-nitrophenylacetylene and diphenyl phosphine oxide are used as raw materials, and the reaction steps are as follows:
a reaction flask was charged with 4-nitrophenylacetylene (0.059 g, 0.4 mmol), phosphorus diphenoxylate (0.243 g, 1.2 mmol), trimethylsilyl isothiocyanate (0.154 g, 1.2 mmol), CuCl2(0.112g, 0.08 mmol), t-butanol peroxide (0.154 g, 1.2 mmol) and acetonitrile (3 mL), at 50 ℃;
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 70%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 7.82 – 7.71 (m, 4H), 7.64 – 7.45 (m, 8H), 7.19 – 7.07 (m, 2H), 6.60 (d, J = 18.9 Hz, 1H)。
example twelve: synthesis of (2- (4-methoxycarbonylphenyl) -2-thiocyano)) vinyldiphenylphosphine oxide
The method takes 4-acetylenyl methyl benzoate and diphenyl phosphine oxide as raw materials, and comprises the following reaction steps:
to a reaction flask was added methyl 4-ethynylbenzoate (0.064, 0.4 mmol), phosphorus diphenoxylate (0.243 g, 1.2 mmol), trimethylsilyl isothiocyanate (0.154 g, 1.2 mmol), CuCl2(0.056g, 0.04 mmol), t-butyl hydroperoxide (0.154 g, 1.2 mmol) and N, N-dimethylformamide (3 mL), at 50 ℃;
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 73%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 7.8 – 7.72 (m, 4H), 7.60 – 7.48 (m, 8H), 6.95 (d, J = 8.8 Hz, 2H), 6.58 (d, J = 18.9 Hz, 1H), 3.89 (s, 3H)。
example thirteen: synthesis of (1, 2-diphenyl-2-thiocyano) ethenyl diphenyl phosphine oxide
Uses tolane and diphenyl phosphine oxide as raw materials, and comprises the following reaction steps:
a reaction flask was charged with tolane (0.071 g, 0.4 mmol), phosphorus diphenoxylate (0.243 g, 1.2 mmol), trimethylsilyl isothiocyanate (0.154 g, 1.2 mmol), CuI2(0.128g, 0.04 mmol), t-butanol peroxide (0.154 g, 1.2 mmol) and N, N-dimethylformamide (3 mL), at 50 ℃;
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 82%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 7.85 – 7.71 (m, 8H), 7.67 – 7.39 (m, 12H)。
example fourteen: synthesis of (1-acetyl-2-phenyl-2-thiocyano) ethenylbiphenylphosphine oxide
1-phenylbutylkyn-3-one and diphenyl phosphine oxide are used as raw materials, and the reaction steps are as follows:
1-Phenylbutyn-3-one (0.058 g, 0.4 mmol), diphenylphosphine (0.081 g, 0.4 mmol), trimethylsilyl isothiocyanate (0.052 g, 0.4 mmol), CuI were added to a reaction flask2(0.256g, 0.08 mmol), t-butanol peroxide (0.154 g, 1.2 mmol) and N, N-dimethylformamide (3 mL), at 50 ℃;
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 74%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 7.91 – 7.82 (m, 4H), 7.64 – 7.58 (m, 2H), 7.56 – 7.46 (m, 7H), 7.43 – 7.39 (m, 2H), 1.38 (s, 3H)。
example fifteen: synthesis of (2- (pyridin-2-yl) -2-thiocyano) ethenylbiphenylphosphine oxide
The method takes 2-ethynylpyridine and diphenyl phosphine oxide as raw materials and comprises the following reaction steps:
2-ethynylpyridine (0.041 g, 0.4 mmol), diphenylphosphine (0.081 g, 0.4 mmol) and isothiocyanate are added into a reaction bottleTrimethylsilyl ester (0.052 g, 0.4 mmol), CuBr2(0.088g, 0.04 mmol), t-butanol peroxide (0.154 g, 1.2 mmol) and N-methylpyrrolidone (3 mL), at 40 ℃;
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 78%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 7.88-7.86 (m, 1H), 7.78 – 7.72 (m, 5H), 7.53 – 7.36 (m, 8H), 6.55 (d, J = 15.9 Hz, 1H)。
example sixteen: synthesis of (2- (thien-2-yl) -2-thiocyano) ethenylbiphenylphosphine oxide
2-ethynyl thiophene and diphenyl phosphine oxide are used as raw materials, and the reaction steps are as follows:
2-ethynylthiophene (0.042 g, 0.4 mmol), phosphorus diphenoxylate (0.081 g, 0.4 mmol), trimethylsilyl isothiocyanate (0.052 g, 0.4 mmol), CuBr were added to the reaction flask2(0.176g, 0.08 mmol), t-butanol peroxide (0.154 g, 1.2 mmol) and N-methylpyrrolidone (3 mL), at 40 ℃;
the crude product obtained after the reaction was completed was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the desired productThe target product (yield 82%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 7.78 – 7.72 (m, 4H), 7.53 – 7.47 (m, 6H), 7.39-7.37 (m, 1H), 7.01-6.81 (m, 2H), 6.59 (d, J = 15.7 Hz, 1H)。
example seventeen: synthesis of (2- (2-phenylethyl) -2-thiocyano) ethenyl diphenylphosphine oxide
4-phenylbut-1-alkyne and diphenyl phosphine oxide are used as raw materials, and the reaction steps are as follows:
4-Phenylbut-1-yne (0.053 g, 0.4 mmol), diphenylphosphine (0.081 g, 0.4 mmol), trimethylsilyl isothiocyanate (0.052 g, 0.4 mmol), CuBr were added to a reaction flask2(0.088g, 0.04 mmol), t-butanol peroxide (0.154 g, 1.2 mmol) and N-methylpyrrolidone (3 mL), at 40 ℃;
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 75%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 7.73 – 7.64 (m,4.3H), 7.61 – 7.39 (m, 10.7H), 7.24 – 7.04 (m,6.4H), 6.49 (d, J = 17.6 Hz, 1H), 6.06 (d, J = 19.4 Hz, 0.4H), 3.32 – 3.26 (m, 2.1H), 3.08 – 3.01 (m, 2.1H), 2.91 – 2.84 (m, 2.1H)。
example eighteen: synthesis of (2- (3-phenylpropyl) -2-thiocyano) ethenylbiphenylphosphine oxide
5-phenylpent-1-alkyne and diphenyl phosphine oxide are used as raw materials, and the reaction steps are as follows:
adding 5-phenylpent-1-yne (0.058 g, 0.4 mmol), diphenylphosphine oxide (0.081 g, 0.4 mmol), trimethylsilyl isothiocyanate (0.052 g, 0.4 mmol), CuSCN (0.05 g, 0.04 mmol), tert-butyl peroxide (0.154 g, 1.2 mmol) and N-methylpyrrolidone (3 mL) into a reaction bottle, and reacting at 50 ℃;
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 77%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 7.73 – 7.64 (m, 2H), 7.61 – 7.39 (m, 9H), 7.24 – 7.04 (m, 4H), 6.49 (d, J = 17.6 Hz, 1H), 3.32 – 3.26 (m, 2H), 3.08 – 3.01 (m, 2H), 2.91 – 2.84 (m, 4H)。
example nineteenth: synthesis of (2-n-pentyl-2-thiocyano) ethenylbiphenylphosphine oxide
The method takes hept-1-alkyne and diphenyl phosphine oxide as raw materials and comprises the following reaction steps:
adding hept-1-alkyne (0.038 g, 0.4 mmol), phosphorus diphenoxylate (0.081 g, 0.4 mmol), trimethylsilyl isothiocyanate (0.052 g, 0.4 mmol), CuSCN (0.10 g, 0.08 mmol), tert-butyl peroxide (0.154 g, 1.2 mmol) and acetone (3 mL) into a reaction bottle, and reacting at 50 ℃;
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 81%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 7.95 – 7.86 (m, 0.9H), 7.78 – 7.69 (m, 5.5H), 7.66 – 7.52 (m, 10H), 7.45 – 7.25 (m, 1.8H), 7.01 (d, J = 19.9 Hz, 0.8H), 6.89 (d, J = 18.0 Hz, 1H), 2.99 – 2.89 (m, 3H), 2.80 – 2.63 (m, 3H), 1.70 – 1.58 (m, 2H), 1.53 – 1.35 (m, 4H), 1.20 – 1.15 (m, 4H), 0.89 – 0.72 (dt, J = 43.5, 6.9 Hz, 6H)。
example twenty: synthesis of (2-cyclopropyl-2-thiocyano) ethenyl diphenylphosphine oxide
The method takes cyclopropyl acetylene and diphenyl phosphine oxide as raw materials, and comprises the following reaction steps:
adding cyclopropyl acetylene (0.095 g, 0.4 mmol), phosphorus diphenoxylate (0.081 g, 0.4 mmol), trimethylsilyl isothiocyanate (0.052 g, 0.4 mmol), CuSCN (0.05 g, 0.04 mmol), tert-butyl peroxide (0.154 g, 1.2 mmol) and acetone (3 mL) into a reaction bottle, and reacting at 60 ℃;
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 71%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 7.73 – 7.64 (m, 4H), 7.61 – 7.39 (m, 6H), 6.49 (d, J = 15.6 Hz, 1H), 3.32 – 3.26 (m, 1H), 3.08 – 3.01 (m, 2H), 2.91 – 2.84 (m, 2H)。
example twenty one: synthesis of dimethyl (2-phenyl-2-thiocyano) vinylphosphate
The method takes phenylacetylene and dimethyl phosphite ester as raw materials, and comprises the following reaction steps:
phenylacetylene (0.041 g, 0.4 mmol), dimethyl phosphite (0.088g, 0.8 mmol), trimethylsilyl isothiocyanate (0.052 g, 0.4 mmol), CuSCN (0.05 g, 0.04 mmol), tert-butyl peroxide (0.154 g, 1.2 mmol) and acetone (3 mL) are added into a reaction flask and reacted at 30 ℃;
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 84%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 7.33-7.17 (m, 5H), 6.62 (d, J = 18.1 Hz, 1H), 3.25 (d, J = 7.8 Hz, 6H)。
example twenty two: synthesis of diethyl (2-phenyl-2-thiocyano) vinylphosphate
The method takes phenylacetylene and diethyl phosphite ester as raw materials, and comprises the following reaction steps:
a reaction flask was charged with phenylacetylene (0.041 g, 0.4 mmol), diethyl phosphite (0.110 g, 0.8 mmol), trimethylsilyl isothiocyanate (0.052 g, 0.4 mmol), CuSCN (0.05 g, 0.04 mmol), t-butanol peroxide (0.154 g, 1.2 mmol) andn-methyl pyrrolidone (3 mL) and reacting at 50 ℃;
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 86%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 7.33-7.17 (m, 5H), 6.62 (d, J = 18.1 Hz, 1H), 4.24-4.14 (m, 4H), 1.36 (t, J = 7.5 Hz, 6H)。
example twenty three: synthesis of (2-phenyl-2-thiocyano)) vinylbis (4-methoxyphenyl) phosphinoxide
The method takes phenylacetylene and diphenyl phosphine oxide as raw materials, and comprises the following reaction steps:
adding phenylacetylene (0.041 g, 0.4 mmol), phosphorus diphenoxylate (0.081 g, 0.4 mmol), trimethylsilyl isothiocyanate (0.052 g, 0.4 mmol), CuSCN (0.05 g, 0.04 mmol), tert-butyl peroxide (0.154 g, 1.2 mmol) and N-methylpyrrolidone (3 mL) into a reaction bottle, and reacting at 50 ℃;
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 88%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 7.79-7.75 (m, 4H), 7.33-7.06 (m, 9H), 6.62 (d, J = 19.1 Hz, 1H), 3.81 (s, 6H)。
example twenty-four: 2-ethoxy-4-mercapto-1-methyl-2-oxo-1H-benzo [1,2 ]]Synthesis of azaphospho-3-diethyl phosphite (4)
2-methylamino phenylacetylene and diethyl phosphite ester are used as raw materials, and the reaction steps are as follows:
2-methylaminophenylacetylene (0.104 g, 0.8 mmol), diethyl phosphite (0.110 g, 0.8 mmol), trimethylsilyl isothiocyanate (0.104 g, 0.8 mmol), CuSCN (0.10 g, 0.08 mmol), t-butanol peroxide (0.154 g, 1.2 mmol) and N-methylpyrrolidone (5 mL) were charged into a reaction flask and reacted at 50 ℃;
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product 24-1 (yield 81%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ9.81 (s, 1H), 7.33-7.17 (m, 5H), 6.62 (d, J = 18.9 Hz, 1H), 4.24-4.14 (m, 4H), 3.86 (s, 3H), 1.36 (t, J = 7.5 Hz, 6H);
fourth, 24-1 (0.978 g, 3 mmol) and acetic acid (30 mL) were charged into a reaction flask, a zinc powder (3.0 g, 45 mmol) was added thereto, and the mixed solution was heated under reflux for 24 hours. Filtering with diatomaceous earth, concentrating the filtrate, adding diethyl ether, washing with water twice, drying with anhydrous sodium sulfate, and concentrating to obtain the product24-2 (yield 98%). Analytical data for the product are as follows:1H NMR (300 MHz, CDCl3): δ9.81 (s, 1H), 7.33-7.17 (m, 5H), 4.54 (d, J = 13.9 Hz, 2H), 4.14-4.04 (m, 4H), 3.86 (s, 3H), 1.36 (t, J = 7.5 Hz, 6H);
fifthly, 24-2 (0.301 g, 1 mmol), triethyl phosphite (0.498 g, 7 mmol), cuprous trifluoromethanesulfonate (0.021 g, 0.1 mmol), di-tert-butyl peroxide (1.022 g, 7 mmol) and N, N-dimethylformamide (5 mL) are added into a reaction bottle, and the reaction is completed at 80 ℃.20 mL of water was added, extracted with ethyl acetate, dried, concentrated, and the crude product was isolated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective compound 3 (yield 78%). Analytical data for the product are as follows:1H NMR (300 MHz, CDCl3): δ9.81 (s, 1H), 7.33-7.17 (m, 5H), 4.61 – 4.58 (m, 1H), 4.14-4.04 (m, 8H), 3.86 (s, 3H), 1.39 – 1.30 (m, 12H);
(6) a sodium ethoxide solution (0.2 g of sodium (9 mmol) dissolved in 30 mL of ethanol) and compound 3 (1.748 g, 4 mmol) were added to a reaction flask, heated under reflux for 15 hours, cooled to room temperature, adjusted to neutral pH with dilute hydrochloric acid, extracted with ethyl acetate, dried, concentrated, and the crude product was isolated by column chromatography (ethyl acetate: petroleum ether = 1:1) to give the target compound 4 (yield 78%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 7.46 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 8.4 Hz, 2H), 4.01 – 3.88 (m, 6H), 3.23 (d, J = 4.7 Hz, 3H), 1.91 (d, J = 3.8 Hz, 1H), 1.12 (dt, J = 6.6, 3.6 Hz, 6H), 0.99 (dt, J = 6.6, 3.5 Hz, 3H)。
example twenty-five: synthesis of 1-methyl-3-thioindolone-2, 2-tetraethyl diphosphite (5)
The compound 3 is used as a raw material, and the reaction steps are as follows:
(1) compound 3 (0.087 g, 0.2 mmol), iodosobenzene (0.088g, 0.4 mmol), tetra-n-butyliodinated amine (0.089 g, 0.24 mmol) and toluene (1 mL) were added to the reaction flask. Reacting at room temperature;
(2) TLC tracing the reaction until the reaction is completely finished;
(3) the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective compound 5 (yield 81%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 7.42 (d, J = 8.1 Hz, 2H), 7.85 (d, J = 8.1 Hz, 2H), 4.01 – 3.84 (m, 8H), 3.14 (d, J = 3.3 Hz, 3H), 1.41 – 1.11 (m, 12H)。
example twenty-six: synthesis of 1, 1-di (diethylphosphonate) heptathione-2 (26-3)
The method takes heptyne and diethyl phosphite ester as raw materials and comprises the following reaction steps:
heptyne (0.077 g, 0.8 mmol) was added to a reaction flask, diethyl phosphite (0.220 g, 1.6 mmol), trimethylsilyl isothiocyanate (0.208 g, 1.6 mmol), CuSCN (0.10 g, 0.08 mmol), t-butanol peroxide (0.205 g, 1.6 mmol) and N-methylpyrrolidone (5 mL) were added and reacted at 50 ℃;
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product 26-1 (yield 82%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 6.43 (d, J = 13.9 Hz, 1H), 4.24 – 4.14 (m, 4H), 3.08 (t, J = 4.7 Hz, 2H), 1.41 – 1.30 (m, 6H), 1.24 (dd, J = 9.3, 7.6 Hz, 6H), 0.85 (t, J = 6.9 Hz, 3H);
26-1 (0.873 g, 3 mmol) and acetic acid (30 mL) were charged into a reaction flask, a zinc powder (3.0 g, 45 mmol) was added thereto, and the mixed solution was heated under reflux for 24 hours. After filtering through celite, the filtrate was concentrated, and then ether was added thereto, washed twice with water, dried over anhydrous sodium sulfate, and concentrated to obtain 26-2 (yield 95%). Analytical data for the product are as follows:1H NMR (300 MHz, CDCl3): δ4.24 – 4.14 (m, 4H), 3.34 (d, J = 15.3 Hz, 2H), 3.08 (t, J = 4.7 Hz, 2H), 1.41 – 1.30 (m, 6H), 1.24 (dd, J = 9.3, 7.6 Hz, 6H), 0.85 (t, J = 6.9 Hz, 3H);
fifthly, 26-2 (0.266 g, 1 mmol), triethyl phosphite (0.498 g, 7 mmol), cuprous trifluoromethanesulfonate (0.021 g, 0.1 mmol), di-tert-butyl peroxide (1.022 g, 7 mmol) and N, N-dimethylformamide (5 mL) are added into a reaction bottle, and the reaction is finished at 80 ℃.20 mL of water was added, extracted with ethyl acetate, dried, concentrated, and the crude product was isolated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective compound 26-3 (yield 78%). Analytical data for the product are as follows:1H NMR (300 MHz, CDCl3): δ 4.24 – 4.14 (m, 8H), 3.34 (d, J = 15.3 Hz, 1H), 3.08 (t, J = 4.7 Hz, 2H), 1.41 – 1.30 (m, 6H), 1.34 – 1.01 (m, 12H), 0.85 (t, J = 6.9 Hz, 3H)。
Claims (2)
1. a preparation method of beta-thiocarbonyl diphosphonic acid derivatives comprises the following steps: dissolving alkyne, phosphorus reagent, trimethylsilyl isothiocyanate, a copper catalyst and peroxide in a solvent, and reacting at 30-70 ℃ to obtain a beta-thiocyanato alkenyl phosphono derivative; then, preparing the beta-thiocarbonylphosphinyl derivatives by taking the beta-thiocyanoalkenylphosphono derivatives as raw materials in the presence of a zinc catalyst and acetic acid; then, preparing the beta-thiophosphoryl diphosphonate derivatives from the beta-thiophosphoryl phosphonyl derivatives serving as raw materials in the presence of phosphite ester, cuprous trifluoromethanesulfonate and di-tert-butyl peroxide;
the beta-thiocyano alkenyl phosphono derivative is shown as the following chemical structural general formula:
the beta-thiocarbonylphosphinyl derivative is shown as the following chemical structural general formula:
the beta-thiocarbonyl diphosphonic acid derivative is shown as the following chemical structural general formula:
the alkyne is n-hept-1-alkyne;
the phosphorus reagent is diethyl phosphite;
the chemical formula of the copper catalyst is CuXnWherein X is one of Cl, Br, I or SCN; n is 1 or 2.
2. The method of claim 1, wherein: according to the molar ratio, alkyne, phosphorus reagent, trimethylsilyl isothiocyanate, copper catalyst and peroxide are 1: 1-3: 0.1-0.3: 1-3; tracking the reaction by thin layer chromatography until the reaction is completely finished; after the reaction is finished, carrying out column chromatography separation and purification treatment on the product; the solvent is selected from one of ethanol, acetonitrile, tetrahydrofuran, acetone, toluene, N-dimethylformamide or N-methylpyrrolidone; the peroxide is tert-butyl peroxide.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910606595.8A CN110272450B (en) | 2017-09-08 | 2017-09-08 | Beta-thiocarbonyl diphosphonic acid derivative and preparation method thereof |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710808044.0A CN107501328B (en) | 2017-09-08 | 2017-09-08 | A kind of β-thiocyanogen alkenyl phosphono analog derivative and preparation method thereof |
CN201910606595.8A CN110272450B (en) | 2017-09-08 | 2017-09-08 | Beta-thiocarbonyl diphosphonic acid derivative and preparation method thereof |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201710808044.0A Division CN107501328B (en) | 2017-09-08 | 2017-09-08 | A kind of β-thiocyanogen alkenyl phosphono analog derivative and preparation method thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CN110272450A CN110272450A (en) | 2019-09-24 |
CN110272450B true CN110272450B (en) | 2021-08-17 |
Family
ID=60696002
Family Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201910606597.7A Active CN110256496B (en) | 2017-09-08 | 2017-09-08 | Beta-thioindolone derivative and preparation method thereof |
CN201910606598.1A Active CN110218229B (en) | 2017-09-08 | 2017-09-08 | Beta-mercapto azaphospho heterocyclic derivative and preparation method thereof |
CN201710808044.0A Active CN107501328B (en) | 2017-09-08 | 2017-09-08 | A kind of β-thiocyanogen alkenyl phosphono analog derivative and preparation method thereof |
CN201910606595.8A Active CN110272450B (en) | 2017-09-08 | 2017-09-08 | Beta-thiocarbonyl diphosphonic acid derivative and preparation method thereof |
Family Applications Before (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201910606597.7A Active CN110256496B (en) | 2017-09-08 | 2017-09-08 | Beta-thioindolone derivative and preparation method thereof |
CN201910606598.1A Active CN110218229B (en) | 2017-09-08 | 2017-09-08 | Beta-mercapto azaphospho heterocyclic derivative and preparation method thereof |
CN201710808044.0A Active CN107501328B (en) | 2017-09-08 | 2017-09-08 | A kind of β-thiocyanogen alkenyl phosphono analog derivative and preparation method thereof |
Country Status (1)
Country | Link |
---|---|
CN (4) | CN110256496B (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109096330B (en) * | 2018-10-08 | 2020-08-14 | 苏州大学 | Trifluoromethyl alkenyl phosphonate and preparation method thereof |
CN109096336B (en) * | 2018-10-08 | 2019-09-27 | 南通纺织丝绸产业技术研究院 | A kind of preparation method and application of benzo phospha naphthalene derivatives |
WO2020073208A1 (en) * | 2018-10-09 | 2020-04-16 | 南通纺织丝绸产业技术研究院 | Method for preparing benzophospho naphthalene derivative, and use thereof |
CN112010722B (en) * | 2020-09-14 | 2023-01-06 | 南通大学 | Synthesis method of E-type beta-thiocyanatelamide derivative |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105503945A (en) * | 2015-12-14 | 2016-04-20 | 苏州大学 | Method for preparing 2-phosphonic acid ester base-1, 3-dicarbonyl derivative |
CN106432329A (en) * | 2016-09-09 | 2017-02-22 | 苏州大学 | Beta-cyano phosphoryl derivatives as well as preparation method and application thereof |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RU2327700C2 (en) * | 1998-09-09 | 2008-06-27 | Метабэйзис Терапьютикс, Инк. | New hetero-aromatic inhibitors of fructose-1,6-bisphosphotase, pharmaceutical compositions containing them and method of inhibiting fructose-1,6-bisphosphotase |
CN105017312B (en) * | 2015-06-26 | 2017-05-10 | 苏州大学 | Preparation method of beta-aminoethylphosphonyl derivatives |
-
2017
- 2017-09-08 CN CN201910606597.7A patent/CN110256496B/en active Active
- 2017-09-08 CN CN201910606598.1A patent/CN110218229B/en active Active
- 2017-09-08 CN CN201710808044.0A patent/CN107501328B/en active Active
- 2017-09-08 CN CN201910606595.8A patent/CN110272450B/en active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105503945A (en) * | 2015-12-14 | 2016-04-20 | 苏州大学 | Method for preparing 2-phosphonic acid ester base-1, 3-dicarbonyl derivative |
CN106432329A (en) * | 2016-09-09 | 2017-02-22 | 苏州大学 | Beta-cyano phosphoryl derivatives as well as preparation method and application thereof |
Non-Patent Citations (1)
Title |
---|
"Inhibitory effect of novel S,N-bisphosphonates on some carcinoma cell lines,osteoarthritis, and chronic inflammation";Azza A. Kamel et al.;《European Journal of Medicinal Chemistry》;20120306;第51卷;第239-249页 * |
Also Published As
Publication number | Publication date |
---|---|
CN110272450A (en) | 2019-09-24 |
CN110218229A (en) | 2019-09-10 |
CN110256496B (en) | 2021-08-17 |
CN110218229B (en) | 2021-08-17 |
CN107501328B (en) | 2019-09-03 |
CN107501328A (en) | 2017-12-22 |
CN110256496A (en) | 2019-09-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN110272450B (en) | Beta-thiocarbonyl diphosphonic acid derivative and preparation method thereof | |
SK15892000A3 (en) | Process for synthesizing cox-2 inhibitors | |
US20080306028A1 (en) | Erianin Salts, Their Preparation Methods and Pharmaceutical Compositions Containing the Same | |
CN101531681A (en) | High-purity minodronic acid and preparation method thereof | |
CN110683975B (en) | Synthesis method of dialkyl amino alkyl dithioformate | |
US20040259922A1 (en) | Epothilone derivatives, a process for their production thereof and their use | |
CA2628098A1 (en) | Process for the preparation of (.omega.-aminoalkylamino)alkyl halides and conversion to amifostine | |
CN110105392A (en) | What a kind of tenofovir Chinese mugwort drew phenol amine efficiently synthesizes technique | |
KR100460828B1 (en) | Process for producing guanidine derivatives, intermediates thereof and their production | |
CN106243183B (en) | Ursolic acid-hydrogen sulfide donor reagent derivatives and its synthetic method | |
JPH0393787A (en) | Pharmaceutical agent having viral action or antiviral action, phospholipid derivative and method of its preparation | |
JPWO2009008345A1 (en) | METAL COMPLEX COMPOUND, CANCER TREATMENT COMPOSITION CONTAINING THE SAME, AND INTERMEDIATE FOR THE METAL COMPLEX COMPOUND | |
CN108129512B (en) | Preparation method of allyl thio or seleno phosphate and phosphonate | |
CN102532199A (en) | Structure and synthesis of novel benzyl amido phosphate prodrug of nucleoside compound | |
CN103755664B (en) | 4-aryl thiophene (selenium) azole compounds and application thereof | |
CN104592254B (en) | The synthetic method of everolimus | |
US11905250B2 (en) | Methods for preparation of jasmonate compounds | |
CN110981911A (en) | Preparation method of tenofovir alafenamide | |
CN115974768B (en) | Preparation method and application of piperlonguminine derivatives containing diaryl urea structure | |
CN111527069A (en) | Quinoline derivatives | |
CN109021014B (en) | Method for synthesizing 2-O- (3-aminopropyl hydrogen phosphoryl) -ascorbic acid | |
CN110078762B (en) | Method for preparing beta-mercapto phosphonyl derivatives | |
Perlman et al. | Synthesis, molecular symmetry, and chemical reactivity of C-aryl-substituted phosphoraziridines | |
TW399055B (en) | 1, 9-diazabicyclo [4.3.0] nona-3, 8-diene derivatives having cardioprotective activity | |
KR20130140077A (en) | Method for producing sanshool |
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 | ||
GR01 | Patent grant | ||
GR01 | Patent grant |