CN104151262B - 4,5-bis-replaces-thiazolamine compound and preparation method thereof - Google Patents
4,5-bis-replaces-thiazolamine compound and preparation method thereof Download PDFInfo
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- CN104151262B CN104151262B CN201410321285.9A CN201410321285A CN104151262B CN 104151262 B CN104151262 B CN 104151262B CN 201410321285 A CN201410321285 A CN 201410321285A CN 104151262 B CN104151262 B CN 104151262B
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- Prior art keywords
- phenyl
- thiazolamine
- bis
- compound
- replace
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Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- -1 4-chloro-phenyl- Chemical group 0.000 claims abstract description 51
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 27
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 claims abstract description 13
- 239000003054 catalyst Substances 0.000 claims abstract description 10
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims abstract description 10
- 229910052751 metal Inorganic materials 0.000 claims abstract description 8
- 239000002184 metal Substances 0.000 claims abstract description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 8
- 239000002904 solvent Substances 0.000 claims abstract description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000000463 material Substances 0.000 claims abstract description 6
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims abstract description 6
- 238000010898 silica gel chromatography Methods 0.000 claims abstract description 6
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims abstract description 5
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims abstract description 5
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims abstract description 5
- 238000005406 washing Methods 0.000 claims abstract description 5
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims abstract description 4
- 239000012141 concentrate Substances 0.000 claims abstract description 4
- 238000000605 extraction Methods 0.000 claims abstract description 4
- 239000012044 organic layer Substances 0.000 claims abstract description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical group CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 18
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical group [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 claims description 12
- 235000003891 ferrous sulphate Nutrition 0.000 claims description 11
- 239000011790 ferrous sulphate Substances 0.000 claims description 11
- 229910000359 iron(II) sulfate Inorganic materials 0.000 claims description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 7
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 6
- 239000012454 non-polar solvent Substances 0.000 claims description 5
- 239000002798 polar solvent Substances 0.000 claims description 5
- 229910016874 Fe(NO3) Inorganic materials 0.000 claims description 3
- 229960003280 cupric chloride Drugs 0.000 claims description 3
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 93
- 239000012265 solid product Substances 0.000 description 28
- 150000001875 compounds Chemical class 0.000 description 19
- 230000000052 comparative effect Effects 0.000 description 17
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 15
- 238000005160 1H NMR spectroscopy Methods 0.000 description 15
- 238000010189 synthetic method Methods 0.000 description 9
- 238000000034 method Methods 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical class NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 6
- 230000000259 anti-tumor effect Effects 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 5
- 239000004215 Carbon black (E152) Substances 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229930195733 hydrocarbon Natural products 0.000 description 4
- 150000002611 lead compounds Chemical class 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- UNEJCSIMFOPSAV-UHFFFAOYSA-N C(=O)=NC=1SC(=CN1)C1=CC=C(C=C1)CN.[O] Chemical compound C(=O)=NC=1SC(=CN1)C1=CC=C(C=C1)CN.[O] UNEJCSIMFOPSAV-UHFFFAOYSA-N 0.000 description 3
- FLSDAQKOVSOHRO-UHFFFAOYSA-N C(=O)=NC=1SC(=CN1)C1=CC=C(C=C1)[N+](=O)[O-].[O] Chemical compound C(=O)=NC=1SC(=CN1)C1=CC=C(C=C1)[N+](=O)[O-].[O] FLSDAQKOVSOHRO-UHFFFAOYSA-N 0.000 description 3
- UUIUIILGPHUZJV-UHFFFAOYSA-N C(=O)=NC=1SC(=CN1)C=1OC=CC1.[O] Chemical compound C(=O)=NC=1SC(=CN1)C=1OC=CC1.[O] UUIUIILGPHUZJV-UHFFFAOYSA-N 0.000 description 3
- MHGOMYLMDNDPHK-UHFFFAOYSA-N C(=O)=NC=1SC(=CN1)CCC.[O] Chemical compound C(=O)=NC=1SC(=CN1)CCC.[O] MHGOMYLMDNDPHK-UHFFFAOYSA-N 0.000 description 3
- 238000006846 Hantzsch Thiazole synthesis reaction Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 230000001629 suppression Effects 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 239000005411 L01XE02 - Gefitinib Substances 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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- SCBDPBCXUZBPGM-UHFFFAOYSA-N [2-amino-5-(furan-2-yl)-1,3-thiazol-4-yl]-phenylmethanone Chemical compound C=1C=COC=1C=1SC(N)=NC=1C(=O)C1=CC=CC=C1 SCBDPBCXUZBPGM-UHFFFAOYSA-N 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 229960002584 gefitinib Drugs 0.000 description 2
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229960001866 silicon dioxide Drugs 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- DFWWBNHGVZGRDN-UHFFFAOYSA-N (2-amino-5-phenyl-1,3-thiazol-4-yl)-(4-methylphenyl)methanone Chemical compound CC1=CC=C(C(=O)C=2N=C(SC2C2=CC=CC=C2)N)C=C1 DFWWBNHGVZGRDN-UHFFFAOYSA-N 0.000 description 1
- JAWMKHVPLLQZHX-UHFFFAOYSA-N (2-amino-5-phenyl-1,3-thiazol-4-yl)-phenylmethanone Chemical compound C=1C=CC=CC=1C=1SC(N)=NC=1C(=O)C1=CC=CC=C1 JAWMKHVPLLQZHX-UHFFFAOYSA-N 0.000 description 1
- YIWGJFPJRAEKMK-UHFFFAOYSA-N 1-(2H-benzotriazol-5-yl)-3-methyl-8-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carbonyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione Chemical compound CN1C(=O)N(c2ccc3n[nH]nc3c2)C2(CCN(CC2)C(=O)c2cnc(NCc3cccc(OC(F)(F)F)c3)nc2)C1=O YIWGJFPJRAEKMK-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- GBVYYYFICXVGLN-UHFFFAOYSA-N C(C1=CC=C(C=C1)OC)(=O)C=1N=C(SC1C1=CC=CC=C1)N Chemical compound C(C1=CC=C(C=C1)OC)(=O)C=1N=C(SC1C1=CC=CC=C1)N GBVYYYFICXVGLN-UHFFFAOYSA-N 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 238000006957 Michael reaction Methods 0.000 description 1
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- VCUFZILGIRCDQQ-KRWDZBQOSA-N N-[[(5S)-2-oxo-3-(2-oxo-3H-1,3-benzoxazol-6-yl)-1,3-oxazolidin-5-yl]methyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C1O[C@H](CN1C1=CC2=C(NC(O2)=O)C=C1)CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F VCUFZILGIRCDQQ-KRWDZBQOSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 241000534944 Thia Species 0.000 description 1
- JAWMENYCRQKKJY-UHFFFAOYSA-N [3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-ylmethyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-en-8-yl]-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]methanone Chemical compound N1N=NC=2CN(CCC=21)CC1=NOC2(C1)CCN(CC2)C(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F JAWMENYCRQKKJY-UHFFFAOYSA-N 0.000 description 1
- BPUYAOAAYQLHKK-UHFFFAOYSA-N [N+](=O)([O-])C1=CC=C(C(=O)C=2N=C(SC2C2=CC=C(C=C2)CN)N)C=C1 Chemical compound [N+](=O)([O-])C1=CC=C(C(=O)C=2N=C(SC2C2=CC=C(C=C2)CN)N)C=C1 BPUYAOAAYQLHKK-UHFFFAOYSA-N 0.000 description 1
- YQCLOJYBGYHQBH-UHFFFAOYSA-N [N+](=O)([O-])C1=CC=C(C(=O)C=2N=C(SC2C2=CC=CC=C2)N)C=C1 Chemical compound [N+](=O)([O-])C1=CC=C(C(=O)C=2N=C(SC2C2=CC=CC=C2)N)C=C1 YQCLOJYBGYHQBH-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 239000011964 heteropoly acid Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- GRHBQAYDJPGGLF-UHFFFAOYSA-N isothiocyanic acid Chemical compound N=C=S GRHBQAYDJPGGLF-UHFFFAOYSA-N 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- SFMJNHNUOVADRW-UHFFFAOYSA-N n-[5-[9-[4-(methanesulfonamido)phenyl]-2-oxobenzo[h][1,6]naphthyridin-1-yl]-2-methylphenyl]prop-2-enamide Chemical compound C1=C(NC(=O)C=C)C(C)=CC=C1N1C(=O)C=CC2=C1C1=CC(C=3C=CC(NS(C)(=O)=O)=CC=3)=CC=C1N=C2 SFMJNHNUOVADRW-UHFFFAOYSA-N 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/40—Unsubstituted amino or imino radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Abstract
The invention discloses a kind of 4,5-bis-and replace-thiazolamine compound, its structural formula is:
; Described R
1for 4-tolyl, 4-chloro-phenyl-, 4-p-methoxy-phenyl, 4-nitrophenyl or propoxy-, R
2for phenyl, 4-tolyl, 4-fluorophenyl, 4-methoxyphenyl, 2-furyl, sec.-propyl, 4-nitrophenyl or n-propyl.The present invention also provides above-mentioned 4 simultaneously, 5-bis-replaces-preparation method of thiazolamine compound, comprise the following steps: by alkene azide compounds, potassium sulfocyanate under solvent and metal catalyst existent condition in 75 ~ 85 DEG C of reactions, after the reaction solution of gained is concentrated, with water and extraction into ethyl acetate, the organic layer of gained is after washing, dry, and Rotary Evaporators concentrates; Gained enriched material carries out silica gel column chromatography, obtains 4,5-bis-and replaces-thiazolamine compound.
Description
Technical field
The invention belongs to the synthetic method of compound, relate generally to 4,5-bis-to replace-thiazolamine compound and preparation method thereof.
Background technology
Thiazole compound is the important heterogeneous ring compound of a class, all has important application at medicine, agricultural, material, life science.Can there is series reaction by amido functional group in aminothiazole compounds, the compound synthesized thus has a wide range of applications in agricultural chemicals, dyestuff etc., as the synthesis of weedicide, monoazo-dispersed dye etc.Thiazolamine compounds is widely used for the medicine synthesizing disease such as treatment tumour, hypertension etc.
Thiazolamine compound is because have important using value, and its synthetic method is paid close attention to always widely, and wherein that the most classical is thiazole synthesis method (Hantzsch, the A. that Hantzsch etc. proposes; Weber, J.H.ChemischeBerichte.1887,20,3118), it, with α-halogenatedketone or alpha-halogen aldehyde and thiocarbamide effect, obtains thiazolamine compounds (formula 1).
But Hantzsch thiazole synthesis method is reacted in acid condition, adopt polar organic solvent, the reaction times is longer, and productive rate neither be very desirable.Descendant has carried out a large amount of improvement to synthetic method on the basis of Hantzsch, (Biswanath, the D. such as Biswanath; Reddy, V.S.JournalofMolecularCatalysisA:Chemical.2006,252,235.) be that catalyzer reacts with heteropolyacid salt AMP; (Yadav, the J.S. such as Yadav; Subba; Reddy, B.V.TetraheronLetters.2008,49,231) use Cu (OTf)
2α-the diazo-ketones of catalysis and the reaction of thiocarbamide.
Except Hantzsch thiazole synthesis method and improvement thereof, (Aoyama, the T. such as Aoyama; Murata, S.; Arai, I.Tetrahedron, 2006,62,14) report and utilize α-halogenatedketone and KSCN/SiO
2-NH
4oAc/Al
2o
3carrier one pot reaction obtains thiazolamine (formula 2); (Pradip, the K.S. such as Pradip; Chandrasekhar, A.; Sridhar, S.; Javed, I.Tetrahedron, 2008,49,1) carry out thia Michael reaction in molecule with isothiocyanic acid and the alkynylamine of band ester group, obtain aminothiazole compounds (formula 3).
Although the synthesis report of thiazolamine is more, the problems such as known synthetic method still also exists that raw material not easily obtains, product yield is low, complex operation poor for applicability for different functional groups.In addition, aforesaid method introduces alkyl, aromatic base, hydrogen or alkoxyl group thiazole 4 usually, and the bibliographical information introducing acyl group or hydrocarbon carbonyl oxygen thiazole ring 4 is less.
Known normally changes the substrate α-halogenatedketone of Hantzsch thiazole synthesis method into 3-halo-1 in the method for thiazole ring 4 introducing acyl group or hydrocarbon carbonyl oxygen, 2-propanedione compounds, thus introduce acyl group (Raihan thiazole ring 4, MustafaJ.etal.AdvancedSynthesis & Catalysis, 2012,354,2251), or α-halogenatedketone is changed into 3-halo-2-oxo-propionates compounds and introduce hydrocarbon carbonyl oxygen (Roppe, JeffreyR thiazole ring 4; Etal.WO2007117778), but the more difficult acquisition of raw material needed for synthesis, and reaction all need be carried out under high temperature reflux condition.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of 4,5-bis-and replaces-thiazolamine compound and preparation method thereof.
In order to solve the problems of the technologies described above, the invention provides a kind of 4,5-bis-and replace-thiazolamine compound, its structural formula is:
Described R
1for 4-tolyl, 4-chloro-phenyl-, 4-p-methoxy-phenyl, 4-nitrophenyl or propoxy-,
R
2for phenyl, 4-tolyl, 4-fluorophenyl, 4-methoxyphenyl, 2-furyl, sec.-propyl, 4-nitrophenyl or n-propyl.
As of the present invention 4,5-bis-replacing-improvement of thiazolamine compound: for following any one:
4-(4-chlorobenzene formacyl)-5-phenyl-thiazolamine,
4-(4-chlorobenzene formacyl)-5-(4-fluorophenyl)-thiazolamine,
4-(4-nitro benzoyl)-5-(4-p-methoxy-phenyl)-thiazolamine,
4-benzoyl-5-(2-furyl)-thiazolamine.
The present invention also provides simultaneously and above-mentioned 4,5-bis-to replace the-preparation method of thiazolamine compound, comprises the following steps successively:
1), by alkene azide compounds, potassium sulfocyanate react in 75 ~ 85 DEG C (being preferably 80 DEG C) under solvent and metal catalyst existent condition, the reaction times is 11 ~ 13 hours (being preferably 12 hours); The mol ratio of alkene azide compounds, potassium sulfocyanate, metal catalyst is 2:4:1;
The structural formula of described alkene azide compounds is:
Described R
1for phenyl, 4-aminomethyl phenyl, 4-chloro-phenyl-, 4-p-methoxy-phenyl, 4-nitrophenyl or propoxy-,
R
2for phenyl, 4-tolyl, 4-fluorophenyl, 4-methoxyphenyl, 2-furyl, sec.-propyl, 4-nitrophenyl or n-propyl;
Remarks illustrate: generally speaking, the solvent of the alkene azide compounds adapted 2.0 ~ 4.0ml of every 0.5mmol;
2), step 1) after the reaction solution of gained is concentrated (namely, except desolventizing), first be cooled to room temperature (15 ~ 30 DEG C), use water and extraction into ethyl acetate again, the organic layer (being positioned at upper strata) of gained is after washing (using saturated common salt water washing), drying, Rotary Evaporators concentrates (until substantially without slipping out liquid);
3), by step 2) gained enriched material carries out silica gel column chromatography, and obtain 4,5-bis-and replace-thiazolamine compound.
As of the present invention 4,5-bis-replacing-and the improvement of the preparation method of thiazolamine compound: described metal catalyst is ferrous sulfate, Fe(NO3)39H2O, cupric chloride.
As of the present invention 4,5-bis-replacing-the further improvement of the preparation method of thiazolamine compound:
Described solvent is polar solvent or non-polar solvent;
Described polar solvent is n-propyl alcohol, Isosorbide-5-Nitrae-dioxane, DMF or Nitromethane 99Min.; Non-polar solvent is toluene.
As of the present invention 4,5-bis-replacing-the further improvement of the preparation method of thiazolamine compound: step 3) silica gel column chromatography be: elutriant is by sherwood oil: the volume ratio of ethyl acetate=2:1 is obtained by mixing.
Contriver passes through FeSO
4.7H
2o etc. have synthesized 4 of novel structure as catalyzer, 5-bis-replaces-thiazolamine compound (as shown in Equation 4), this synthetic method mild condition, yield is high, convenient post-treatment, the cheap pollution of used catalyst is few, is raw materials usedly easy to get, replace for efficiently synthesizing 4,5-bis--thiazolamine compound provides a kind of simple method.In addition; this synthetic method introduces acyl group or hydrocarbon oxygen acyl group thiazole ring 4; for the bioactive compound library that has building novel structure provides possibility; find that the compound synthesized has extracorporeal suppression tumor cell activity simultaneously; for finding that the lead compound with anti-tumor activity has great importance, synthetic method of the present invention has no bibliographical information.
Specifically, the present invention be 4,5-bis-replace-synthesis of thiazolamine compound provides a kind of new method, (is such as FeSO by potassium sulfocyanate, alkene triazo-compound, metal catalyst
4.7H
2o) one kettle way carries out ring-closure reaction in 75-85 DEG C (being preferably 80 DEG C), and high yield (the highest yield 98%) obtains target compound 4, and 5-bis-replaces-thiazolamine compound.
Further, provided by the present invention 4,5-bis-replace-synthetic route of thiazolamine compound as shown in Equation 5.
Wherein R
1for phenyl, 4-aminomethyl phenyl, 4-chloro-phenyl-, 4-p-methoxy-phenyl, 4-nitrophenyl, propoxy-, R
2for phenyl, 4-aminomethyl phenyl, 4-fluorophenyl, 4-p-methoxy-phenyl, 2-furyl, sec.-propyl, 4-nitrophenyl, n-propyl.
Alkene triazo-compound (I), potassium sulfocyanate (II) and ferrous sulfate (III) react in 75-85 DEG C (being preferably 80 DEG C) in the presence of solvent, obtain target compound (IV), solvent for use selects polar solvent or non-polar solvent, and products therefrom obtains pure compound by silica gel column chromatography.
Provided by the invention 4,5-bis-to replace-thiazolamine compou nd synthesis method has following characteristics:
(1) present method used catalyst is cheap and easy to get, and environmental pollution is less;
(2) temperature of reaction is gentle, does not need high temperature reflux, safe ready;
(3) productive rate is high, and most of products collection efficiency is more than 85%.
Alkene azide compounds is the important synthon of a class, is widely used, has reactive behavior high, the feature that speed of response is fast in the synthesis of heterogeneous ring compound, and the reaction that alkene azide compounds participates in is general gentleer.Therefore, the present invention for raw material with potassium sulfocyanate, ferrous sulfate, alkene azide compounds, synthesizes 4,5-bis-in a mild condition and replaces-thiazolamine compound.This synthetic method is carried out under 75-85 DEG C (being preferably 80 DEG C), and synthetic method is novel, has no bibliographical information; The compound structure of synthesis is novel, has no bibliographical information; The compound of synthesis has extracorporeal suppression tumor cell activity, is desirable antitumor lead compound.
In sum, 4,5-bis-of gained of the present invention replace-and the purposes of thiazolamine compound is antitumor lead compound.
Embodiment
Below will the present invention is further illustrated by embodiment.
Embodiment 1,4-(4-chlorobenzene formacyl)-5-phenyl-thiazolamine (m1)
By 1-rubigan-2-nitrine-3-phenyl-2-propylene-1-ketone 141.9mg (0.5mmol), potassium sulfocyanate 97.2mg (1mmol), add in reaction flask, after add CH
3cH
2cH
2oH (n-propyl alcohol) 2.0ml, ferrous sulfate 69.5mg (0.25mmol), after reinforced, 80 DEG C of stirring reactions 12 hours, TLC detection reaction (sherwood oil: the volume ratio of ethyl acetate=1:1).
Remarks illustrate: when TLC detection display 1-rubigan-2-nitrine-3-phenyl-2-propylene-1-ketone disappears, and illustrate that reaction terminates.
After reaction terminates, concentrated removing n-propyl alcohol, be cooled to room temperature, add 60ml water, reaction solution 3 × 20mL extraction into ethyl acetate three times, with 3 × 30mL saturated common salt water washing three times after organic layer (being positioned at upper strata) merges, then uses anhydrous sodium sulphate (2.0g) drying 30 minutes, Rotary Evaporators concentrates (when slipping out liquid until essentially no), obtains enriched material;
Enriched material column chromatography (sherwood oil: the volume ratio of ethyl acetate=2:1), the concrete technology parameter of described column chromatography is as follows:
Select silicagel column (the 200-300 object silica gel of 30g is housed) as chromatography column;
Using sherwood oil: ethyl acetate=2:1 is as elutriant; Flow velocity is 3mL/min; Collect the elutriant of 30min ~ the 40min; Then, after Rotary Evaporators removes desolventizing (that is, elutriant), product 4-(4-chlorobenzene formacyl)-5-phenyl-thiazolamine 153.9mg is obtained, yield 98%.
The structural formula of this 4-(4-chlorobenzene formacyl)-5-phenyl-thiazolamine is:
Yellowsolid；mp:218.6-219.5℃；
1HNMR(500MHz,DMSO)δ7.87(d,J＝8.48,2H),7.54(d,J＝8.47,2H),7.39(s,2H),7.30-7.24(m,5H)；
13CNMR(125MHz,DMSO)δ189.11,166.13,143.04,137.93,135.90,131.55,130.98,130.11,128.58,128.54,128.46,127.75；HRMS(ESI):m/zcalcdforC
16H
11ClN
2OS[M+H]
+:315.0359,found:315.0359。
Be below the control experiment of different condition:
Comparative example 1-1, within 12 hours, make 80 DEG C of stirring reactions into 20 DEG C of stirring reactions 24 hours, all the other are with embodiment 1.Obtain yellow solid product 4-(4-chlorobenzene formacyl)-5-phenyl-thiazolamine 0mg, yield 0%.
Comparative example 1-2, within 12 hours, make 80 DEG C of stirring reactions into 60 DEG C of stirring reactions 18 hours, all the other are with embodiment 1.Obtain yellow solid product 4-(4-chlorobenzene formacyl)-5-phenyl-thiazolamine 147.6mg, yield 94%.
Comparative example 1-3, within 12 hours, make 80 DEG C of stirring reactions into 100 DEG C of stirring reactions 9 hours, all the other are with embodiment 1.Obtain yellow solid product 4-(4-chlorobenzene formacyl)-5-phenyl-thiazolamine 150.7mg, yield 96%.
Comparative example 1-4, make ferrous sulfate into 0.1 equivalent by 0.5 equivalent, all the other are with embodiment 1.Obtain yellow solid product 4-(4-chlorobenzene formacyl)-5-phenyl-thiazolamine 56.5mg, yield 36%.
Comparative example 1-5, make ferrous sulfate into 0.3 equivalent by 0.5 equivalent, all the other are with embodiment 1.Obtain yellow solid product 4-(4-chlorobenzene formacyl)-5-phenyl-thiazolamine 131.9mg, yield 84%.
Comparative example 1-6, make ferrous sulfate into 1 equivalent by 0.5 equivalent, all the other are with embodiment 1.Obtain yellow solid product 4-(4-chlorobenzene formacyl)-5-phenyl-thiazolamine 153.9mg, yield 98%.
Comparative example 1-7, replace n-propyl alcohol with toluene, all the other are with embodiment 1.Obtain yellow solid product 4-(4-chlorobenzene formacyl)-5-phenyl-thiazolamine 138.2mg, yield 88%.
Comparative example 1-8, use Isosorbide-5-Nitrae-dioxane replace n-propyl alcohol, and all the other are with embodiment 1.Obtain yellow solid product 4-(4-chlorobenzene formacyl)-5-phenyl-thiazolamine 149.2mg, yield 95%.
Comparative example 1-9, replace n-propyl alcohol with water, all the other are with embodiment 1.Obtain yellow solid product 4-(4-chlorobenzene formacyl)-5-phenyl-thiazolamine 0mg, yield 0%.
Comparative example 1-10, replace n-propyl alcohol with Nitromethane 99Min., all the other are with embodiment 1.Obtain yellow solid product 4-(4-chlorobenzene formacyl)-5-phenyl-thiazolamine 146.0mg, yield 93%.
Comparative example 1-11, replace n-propyl alcohol with DMF (DMF), all the other are with embodiment 1.Obtain yellow solid product 4-(4-chlorobenzene formacyl)-5-phenyl-thiazolamine 138.2mg, yield 88%.
Comparative example 1-12, replace ferrous sulfate with Fe(NO3)39H2O, molar weight is constant, and all the other are with embodiment 1.Obtain yellow solid product 4-(4-chlorobenzene formacyl)-5-phenyl-thiazolamine 44.0mg, yield 28%.
Comparative example 1-13, replace ferrous sulfate with cuprous cyanide, molar weight is constant, and all the other are with embodiment 1.Obtain yellow solid product 4-(4-chlorobenzene formacyl)-5-phenyl-thiazolamine 0mg, yield 0%.
Comparative example 1-14, replace ferrous sulfate with cupric chloride, molar weight is constant, and all the other are with embodiment 1.Obtain yellow solid product 4-(4-chlorobenzene formacyl)-5-phenyl-thiazolamine 65.9mg, yield 42%.
The use of comparative example 1-15, cancellation catalyzer, all the other are with embodiment 1.Obtain yellow solid product 4-(4-chlorobenzene formacyl)-5-phenyl-thiazolamine 0mg, yield 0%.
Comparative example 1-16, make potassium sulfocyanate into 1 equivalent by 2 equivalents, all the other are with embodiment 1.Obtain yellow solid product 4-(4-chlorobenzene formacyl)-5-phenyl-thiazolamine 130.3mg, yield 83%.
Comparative example 1-17, make potassium sulfocyanate into 3 equivalents by 2 equivalents, all the other are with embodiment 1.Obtain yellow solid product 4-(4-chlorobenzene formacyl)-5-phenyl-thiazolamine 153.9mg, yield 98%.
Embodiment 2,4-benzoyl-5-phenyl-thiazolamine (m2)
Replace 1-rubigan-2-nitrine-3-phenyl-2-propylene-1-ketone with 1-phenyl-2-nitrine-3-phenyl-2-propylene-1-ketone, molar weight is constant, and all the other are equal to embodiment 1.Obtain yellow solid product 4-benzoyl-5-phenyl-thiazolamine 128.8mg, yield 92%.
Its structural formula is:
Yellowsolid；mp:160.4-160.8℃；
1HNMR(500MHz,DMSO)δ7.84(d,J＝7.05,2H),7.59(t,J＝6.88,1H),7.47(d,J＝7.31,2H),7.35-7.24(m,7H)；
13CNMR(125MHz,DMSO)δ190.76,166.14,143.60,137.12,133.12,131.11,129.66,128.99,128.56,128.39,128.35,127.59；HRMS(ESI):m/zcalcdforC
16H
12N
2OS[M+H]
+:281.0749,found:281.0748。
Embodiment 3,4-(4-methyl benzoyl)-5-phenyl-thiazolamine (m3)
Replace 1-rubigan-2-nitrine-3-phenyl-2-propylene-1-ketone with 1-p-methylphenyl-2-nitrine-3-phenyl-2-propylene-1-ketone, molar weight is constant, and all the other are equal to embodiment 1.Obtain yellow solid product 4-(4-methyl benzoyl)-5-phenyl-thiazolamine 138.2mg, yield 94%.
Its structural formula is:
Yellowsolid；mp:189.4-189.9℃；
1HNMR(500MHz,DMSO)δ7.75(d,J＝8.07,2H),7.33(s,2H),7.28-7.21(m,7H),2.35(s,3H)；
13CNMR(125MHz,DMSO)δ190.63,166.21,143.88,143.74,134.45,131.18,129.85,128.98,128.60,128.19,127.91,127.47,21.22；HRMS(ESI):m/zcalcdforC
17H
14N
2OS[M+H]
+:295.0905,found:295.0907。
Embodiment 4,4-(4-anisoyl)-5-phenyl-thiazolamine (m4)
Replace 1-rubigan-2-nitrine-3-phenyl-2-propylene-1-ketone with 1-p-methoxyphenyl-2-nitrine-3-phenyl-2-propylene-1-ketone, molar weight is constant, and all the other are equal to embodiment 1.Obtain yellow solid product 4-(4-anisoyl)-5-phenyl-thiazolamine 139.5mg, yield 90%.
Its structural formula is:
Yellowsolid；mp:220.5-220.9℃；
1HNMR(500MHz,DMSO)δ7.84(d,J＝8.89,2H),7.35(s,2H),7.29-7.20(m,5H),7.00(d,J＝8.92,2H),3.82(s,3H)；
13CNMR(125MHz,DMSO)δ189.66,166.25,163.32,144.08,132.15,131.25,129.64,128.61,128.05,127.36,127.10,113.76,55.56；HRMS(ESI):m/zcalcdforC
17H
14N
2O
2S[M+H]
+:311.0854,found:311.0855。
Embodiment 5,4-(4-nitro benzoyl)-5-(4-aminomethyl phenyl)-thiazolamine (m5)
Replace 1-rubigan-2-nitrine-3-phenyl-2-propylene-1-ketone with 1-p-nitrophenyl-2-nitrine-3-p-methylphenyl-2-propylene-1-ketone, molar weight is constant, and all the other are equal to embodiment 1.Obtain yellow solid product 4-(4-nitro benzoyl)-5-(4-aminomethyl phenyl)-thiazolamine 142.4mg, yield 84%.
Its structural formula is:
Yellowsolid；mp:190.4-190.9℃；
1HNMR(500MHz,DMSO)δ8.28(d,J＝8.87,2H),8.04(d,J＝8.88,2H),7.38(s,2H),7.26(d,J＝8.11,2H),7.13(d,J＝7.96,2H),2.27(s,3H)；
13CNMR(125MHz,DMSO)δ188.33,165.66,149.38,143.02,142.05,137.71,133.11,130.81,129.05,128.88,127.89,123.29,20.73；HRMS(ESI):m/zcalcdforC
17H
13N
3O
3S[M+H]
+:340.0756,found:340.0758。
Embodiment 6,4-(4-chlorobenzene formacyl)-5-(4-fluorophenyl)-thiazolamine (m6)
Replace 1-rubigan-2-nitrine-3-phenyl-2-propylene-1-ketone with 1-rubigan-2-nitrine-3-to fluorophenyl-2-propylene-1-ketone, molar weight is constant, and all the other are equal to embodiment 1.Obtain faint yellow solid shape product 4-(4-chlorobenzene formacyl)-5-(4-fluorophenyl)-thiazolamine 152.7mg, yield 92%.
Its structural formula is:
Paleyellowsolid；mp:197.4-197.7℃；
1HNMR(500MHz,DMSO)δ7.87(d,J＝8.31,2H),7.54(d,J＝8.27,2H),7.40-7.35(m,4H),7.15(t,J＝8.65,2H)；
13CNMR(125MHz,DMSO)δ188.71,165.99,162.61,160.65,143.12,137.87,135.99,131.62,130.93,130.87,129.54,128.40,127.47,127.44,115.53,115.36；HRMS(ESI):m/zcalcdforC
16H
10ClFN
2OS[M+H]
+:333.0265,found:333.0264。
Embodiment 7,4-(4-nitro benzoyl)-5-(4-p-methoxy-phenyl)-thiazolamine (m7)
Replace 1-rubigan-2-nitrine-3-phenyl-2-propylene-1-ketone with 1-p-nitrophenyl-2-nitrine-3-p-methoxyphenyl-2-propylene-1-ketone, molar weight is constant, and all the other are equal to embodiment 1.Obtain orange solids shape product 4-(4-nitro benzoyl)-5-(4-p-methoxy-phenyl)-thiazolamine 152.7mg, yield 86%.
Its structural formula is:
Orangesolid；mp:217.8-218.3℃；
1HNMR(500MHz,DMSO)δ8.27(d,J＝8.59,2H),8.03(d,J＝8.60,2H),7.33-7.32(m,4H),6.89(d,J＝8.60,2H),3.74(s,3H)；
13CNMR(125MHz,DMSO)δ188.15,165.27,159.24,149.29,143.26,141.69,133.57,130.79,130.49,123.23,122.97,113.90,55.20；HRMS(ESI):m/zcalcdforC
17H
13N
3O
4S[M+H]
+:356.0705,found:356.0708。
Embodiment 8,4-(4-nitro benzoyl)-5-phenyl-thiazolamine (m8)
Replace 1-rubigan-2-nitrine-3-phenyl-2-propylene-1-ketone with 1-p-nitrophenyl-2-nitrine-3-phenyl-2-propylene-1-ketone, molar weight is constant, and all the other are equal to embodiment 1.Obtain red solid product 4-(4-nitro benzoyl)-5-phenyl-thiazolamine 130.0mg, yield 80%.
Its structural formula is:
Redsolid；mp:215.3-215.8℃；
1HNMR(500MHz,DMSO)δ8.28(d,J＝8.63,2H),8.04(d,J＝8.60,2H),7.42(s,2H),7.37(d,J＝6.89,2H),7.33-7.27(m,3H)；
13CNMR(125MHz,DMSO)δ188.41,166.00,149.44,142.90,142.40,132.73,130.87,130.82,129.01,128.53,128.13,123.33；HRMS(ESI):m/zcalcdforC
16H
11N
3O
3S[M+H]
+:326.0599,found:326.0598。
Embodiment 9,4-benzoyl-5-(2-furyl)-thiazolamine (m9)
Replace 1-rubigan-2-nitrine-3-phenyl-2-propylene-1-ketone with 1-phenyl-2-nitrine-3-(2-furyl)-2-propylene-1-ketone, molar weight is constant, and all the other are equal to embodiment 1.Obtain brown solid product 4-benzoyl-5-(2-furyl)-thiazolamine 120.2mg, yield 89%.
Its structural formula is:
Brownsolid；mp:115.4-115.8℃；
1HNMR(500MHz,DMSO)δ7.88(d,J＝7.22,2H),7.67(d,J＝0.99,1H),7.60(t,J＝7.35,1H),7.50-7.47(m,4H),6.94(d,J＝3.18,1H),6.53(d,J＝1.51,1H)；
13CNMR(125MHz,DMSO)δ189.16,165.50,145.66,143.21,142.91,137.67,132.72,129.67,128.17,120.91,112.15,109.53；HRMS(ESI):m/zcalcdforC
14H
10N
2O
2S[M+H]
+:271.0541,found:271.0542。
Embodiment 10,4-benzoyl-5-sec.-propyl-thiazolamine (m10)
Replace 1-rubigan-2-nitrine-3-phenyl-2-propylene-1-ketone with 1-phenyl-2-nitrine-3-sec.-propyl-2-propylene-1-ketone, molar weight is constant, and all the other are equal to embodiment 1.Obtain faint yellow solid shape product 4-benzoyl-5-sec.-propyl-thiazolamine 114.4mg, yield 93%.
Its structural formula is:
Paleyellowsolid；mp:115.3-115.7℃；
1HNMR(500MHz,DMSO)δ7.90(d,J＝7.48,2H),7.57(t,J＝7.33,1H),7.47(t,J＝7.58,2H),7.01(s,2H),3.71-3.63(m,1H),1.22(d,J＝6.75,6H)；
13CNMR(125MHz,DMSO)δ189.22,163.74,145.40,142.51,138.67,132.12,129.68,127.91,27.09,24.95；HRMS(ESI):m/zcalcdforC
13H
14N
2OS[M+H]
+:247.0905,found:247.0905。
Embodiment 11,4-third oxygen carbonyl-5-(4-aminomethyl phenyl)-thiazolamine (m11)
Replace 1-rubigan-2-nitrine-3-phenyl-2-propylene-1-ketone with 2-nitrine-3-p-methylphenyl-ethyl propenoate, molar weight is constant, and all the other are with embodiment 1.Obtain white solid product 4-third oxygen carbonyl-5-(4-aminomethyl phenyl)-thiazolamine 131.1mg, yield 95%.
Its structural formula is:
Whitesolid；mp:123.9-124.3℃；
1HNMR(500MHz,DMSO)δ7.27(d,J＝7.89,2H),7.23(s,2H),7.17(d,J＝7.81,2H),3.99(t,J＝6.56,2H),2.31(s,3H),1.52-1.45(m,2H),0.74(t,J＝7.37,3H)；
13CNMR(125MHz,DMSO)δ165.51,162.19,137.46,135.68,132.46,129.28,128.65,128.27,65.61,21.35,20.77,10.19；HRMS(ESI):m/zcalcdforC
14H
16N
2O
2S[M+H]
+:277.1011,found:277.1015。
Embodiment 12,4-third oxygen carbonyl-5-(4-nitrophenyl)-thiazolamine (m12)
Replace 1-rubigan-2-nitrine-3-phenyl-2-propylene-1-ketone with 2-nitrine-3-p-nitrophenyl-ethyl propenoate, molar weight is constant, and all the other are equal to embodiment 1.Obtain yellow solid product 4-third oxygen carbonyl-5-(4-nitrophenyl)-thiazolamine 145.9mg, yield 83%.
Its structural formula is:
Yellowsolid；mp:153.8-154.2℃；
1HNMR(500MHz,DMSO)δ8.21(d,J＝8.24,2H),7.67(d,J＝8.20,2H),7.55(s,2H),4.04(t,J＝5.97,2H),1.53-1.49(m,2H),0.74(t,J＝7.02,3H)；
13CNMR(125MHz,DMSO)δ167.01,161.97,146.47,138.25,137.87,130.46,128.72,123.29,66.06,21.26,10.15；HRMS(ESI):m/zcalcdforC
13H
13N
3O
4S[M+H]
+:308.0705,found:308.0707。
Embodiment 13,4-third oxygen carbonyl-5-(4-p-methoxy-phenyl)-thiazolamine (m13)
Replace 1-rubigan-2-nitrine-3-phenyl-2-propylene-1-ketone with 2-nitrine-3-p-methoxyphenyl-ethyl propenoate, molar weight is constant, and all the other are equal to embodiment 1.Obtain white solid product 4-third oxygen carbonyl-5-(4-p-methoxy-phenyl)-thiazolamine 138.7mg, yield 95%.
Its structural formula is:
Whitesolid；mp:169.5-169.9℃；
1HNMR(500MHz,DMSO)δ7.32(d,J＝8.55,2H),7.21(s,2H),6.92(d,J＝8.61,2H),3.99(t,J＝6.58,2H),3.77(s,3H),1.53-1.46(m,2H),0.75(t,J＝7.37,3H)；
13CNMR(125MHz,DMSO)δ165.19,162.14,159.12,135.33,132.72,130.78,123.33,113.54,65.56,55.20,21.37,10.23；HRMS(ESI):m/zcalcdforC
14H
16N
2O
3S[M+H]
+:293.0960,found:293.0963。
Embodiment 14,4-third oxygen carbonyl-5-(2-furyl)-thiazolamine (m14)
Replace 1-rubigan-2-nitrine-3-phenyl-2-propylene-1-ketone with 2-nitrine-3-(2-furyl)-ethyl propenoate, molar weight is constant, and all the other are equal to embodiment 1.Obtain brown solid product 4-third oxygen carbonyl-5-(2-furyl)-thiazolamine 113.4mg, yield 90%.
Its structural formula is:
Brownsolid；mp:100.7-101.1℃；
1HNMR(500MHz,DMSO)δ7.70(s,1H),7.43(s,2H),7.12(d,J＝3.30,1H),6.58(s,1H),4.13(t,J＝6.71,2H),1.67-1.60(m,2H),0.89(t,J＝7.37,3H)；
13CNMR(125MHz,DMSO)δ165.32,162.07,145.36,143.04,134.93,122.82,112.28,110.83,65.92,21.54,10.30；HRMS(ESI):m/zcalcdforC
11H
12N
2O
3S[M+H]
+:253.0647,found:253.0647。
Embodiment 15,4-third oxygen carbonyl-5-n-propyl-thiazolamine (m15)
Replace 1-rubigan-2-nitrine-3-phenyl-2-propylene-1-ketone with 2-nitrine-3-n-propyl-ethyl propenoate, molar weight is constant, and all the other are equal to embodiment 1.Obtain white solid product 4-third oxygen carbonyl-5-n-propyl-thiazolamine 102.6mg, yield 90%.
Its structural formula is:
Whitesolid；mp:92.3-92.7℃；
1HNMR(500MHz,DMSO)δ7.00(s,2H),4.09(t,J＝6.61,2H),2.93(t,J＝7.51,2H),1.68-1.61(m,2H),1.58-1.50(m,2H),0.93-0.88(m,6H)；
13CNMR(125MHz,DMSO)δ163.96,162.13,137.68,135.97,65.40,28.31,24.47,21.60,13.51,10.41；HRMS(ESI):m/zcalcdforC
10H
16N
2O
2S[M+H]
+:229.1011,found:229.1009。
Anti-tumor activity is tested
Experiment, with A431 (people's epidermal carcinoma cell) for test cell strain, adopt mtt assay antitumor activity evaluation is carried out to above-claimed cpd.Test-compound is made into after certain concentration and man―machine systems incubate altogether, measures its inhibiting rate to JEG-3, the results are shown in Table 1.
Detection method is specific as follows:
1. collect the A431 cell of logarithmic phase growth, adjustment concentration of cell suspension is 1*10
4/ hole;
2. add compound, make the final concentration of this compound reach 20umol/L;
3.37 DEG C, 5%CO
2hatch 44 hours;
4. every hole adds the MTT solution (5mg/ml prepares with PBS, pH=7.4) of 20ul, continues cultivation 4 hours;
5. centrifugal 6min, removing supernatant liquor, adds the every hole 150ul of DMSO, and shaking table low speed vibrations 10min, measures each hole light absorption value at enzyme-linked immunosorbent assay instrument OD570nm (630nm calibration);
The calculation formula of inhibiting rate is: cell inhibitory rate=1-(dosing group OD value-return to zero hole OD value)/(control group OD value-return to zero hole OD value).
Table 1 compound is to the inhibiting rate of A431 tumour cell
| Compound | Inhibiting rate (%) | Compound | Inhibiting rate (%) |
| m1 | 70 | m9 | 67 |
| m2 | 53 | m10 | 32 |
| m3 | 50 | m11 | 20 |
| m4 | 55 | m12 | 22 |
| m5 | 48 | m13 | 27 |
| m6 | 72 | m14 | 30 |
| m7 | 62 | m15 | 10 |
| m8 | 54 | Gefitinib (contrast) | 58 |
Part of compounds (m1, m6, m7, m9) the extracorporeal suppression tumor cell activity of synthesizing as can be seen from Table 1 is greater than contrast Gefitinib, the compound of display synthesis is the antitumor lead compound of structure novel, further structural modification is carried out to it, is expected to the antitumor drug candidate finding novel structure.
Finally, it is also to be noted that what enumerate above is only several specific embodiments of the present invention.Obviously, the invention is not restricted to above embodiment, many distortion can also be had.All distortion that those of ordinary skill in the art can directly derive from content disclosed by the invention or associate, all should think protection scope of the present invention.
Claims (3)
1.4,5-bis-replaces-preparation method of thiazolamine compound, it is characterized in that comprising the following steps successively:
1), by alkene azide compounds, potassium sulfocyanate under solvent and metal catalyst existent condition in 75 ~ 85 DEG C of reactions, the reaction times is 11 ~ 13 hours; The mol ratio of alkene azide compounds, potassium sulfocyanate, metal catalyst is 2:4:1;
Described metal catalyst is ferrous sulfate, Fe(NO3)39H2O or cupric chloride;
The structural formula of described alkene azide compounds is:
Described R
1for phenyl, 4-aminomethyl phenyl, 4-chloro-phenyl-, 4-p-methoxy-phenyl, 4-nitrophenyl or propoxy-,
R
2for phenyl, 4-tolyl, 4-fluorophenyl, 4-methoxyphenyl, 2-furyl, sec.-propyl, 4-nitrophenyl or n-propyl;
2), step 1) after the reaction solution of gained is concentrated, with water and extraction into ethyl acetate, the organic layer of gained is after washing, dry, and Rotary Evaporators concentrates;
3), by step 2) gained enriched material carries out silica gel column chromatography, and obtain 4,5-bis-and replace-thiazolamine compound; Its structural formula is:
2. according to claim 14,5-bis-replace-preparation method of thiazolamine compound, it is characterized in that:
Described solvent is polar solvent or non-polar solvent;
Described polar solvent is n-propyl alcohol, Isosorbide-5-Nitrae-dioxane, DMF or Nitromethane 99Min.; Non-polar solvent is toluene.
3. according to claim 24,5-bis-replace-preparation method of thiazolamine compound, it is characterized in that: described step 3) silica gel column chromatography be:
Elutriant is by sherwood oil: the volume ratio of ethyl acetate=2:1 is obtained by mixing.
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| CN104910095B (en) * | 2015-06-29 | 2017-01-04 | 浙江大学 | The preparation method of 4-replacement-thiazolamine compound |
| CN104910096B (en) * | 2015-07-01 | 2017-01-04 | 浙江大学 | 4-replaces the preparation method of-5-thiocyanogen-thiazolamine compound |
| CN105524013B (en) * | 2016-02-02 | 2018-05-08 | 浙江大学 | 4,5- bis- substitutes the preparation method of -2- substituted-amino thiazolium compounds |
| CN105833911B (en) * | 2016-04-06 | 2018-03-09 | 上海应用技术学院 | The Cr Anderson types heteropolyacid catalyst of 1 Phenethylthiourea modification, preparation method and applications |
| CN105665019B (en) * | 2016-04-06 | 2018-03-02 | 上海应用技术学院 | (S) the thiourea modified Mn Anderson types heteropolyacid catalyst of 1 (phenylpropyl of 3 hydroxyl 1), preparation method and applications |
| CN105772088B (en) * | 2016-04-06 | 2018-07-10 | 上海应用技术学院 | (S) Mn-Anderson types heteropolyacid catalyst thiourea modified -1- (1- phenethyls), preparation method and applications |
| CN105772086B (en) * | 2016-04-06 | 2018-03-30 | 上海应用技术学院 | (S) the thiourea modified Mn Anderson types heteropolyacid catalyst of 1 (isopropyl of 1 ethoxy 1), preparation method and applications |
| CN105772102B (en) * | 2016-04-06 | 2018-05-15 | 上海应用技术学院 | (R) Mn-Anderson types heteropolyacid catalyst thiourea modified -1- (1- (2- naphthyls) ethyl), preparation method and applications |
| CN105854941B (en) * | 2016-04-06 | 2018-07-10 | 上海应用技术学院 | (S) Cr-Anderson types heteropolyacid catalyst thiourea modified -1- (1- phenethyls), preparation method and applications |
| CN105833910B (en) * | 2016-04-06 | 2018-03-30 | 上海应用技术学院 | (R) the thiourea modified Cr Anderson types heteropolyacid catalyst of 1 (phenethyl of 2 hydroxyl 1), preparation method and applications |
| CN105797771B (en) * | 2016-04-06 | 2018-05-15 | 上海应用技术学院 | (R) Mn-Anderson types heteropolyacid catalyst thiourea modified -1- (1- phenethyls), preparation method and applications |
| CN105772085B (en) * | 2016-04-06 | 2018-04-13 | 上海应用技术学院 | (S) the thiourea modified Cr Anderson types heteropolyacid catalyst of 1 (1 ethoxy, 1 isopropyl), preparation method and applications |
| CN108947930A (en) * | 2018-07-19 | 2018-12-07 | 浙江大学 | The synthetic method of bis- substitution -2- amino-thiazol compound of 4,5- |
| CN109265411A (en) * | 2018-11-08 | 2019-01-25 | 武汉轻工大学 | 4- hydroxyl-3- substitution-thiazolidine -2 -one class compound preparation method |
| CN110117263B (en) * | 2019-06-11 | 2020-12-25 | 湖南中医药大学 | 2-amino-5-acyl thiazole derivative and synthetic method thereof |
| CN115215817B (en) * | 2022-07-06 | 2023-09-19 | 武汉工程大学 | 2-aminothiazole-4-acetic acid derivative and preparation method and application thereof |
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