CN112110863A - Sulfonyl fluoride compound, preparation method thereof and method for preparing sulfonamide compound through sulfonyl fluoride compound - Google Patents
Sulfonyl fluoride compound, preparation method thereof and method for preparing sulfonamide compound through sulfonyl fluoride compound Download PDFInfo
- Publication number
- CN112110863A CN112110863A CN202010879059.8A CN202010879059A CN112110863A CN 112110863 A CN112110863 A CN 112110863A CN 202010879059 A CN202010879059 A CN 202010879059A CN 112110863 A CN112110863 A CN 112110863A
- Authority
- CN
- China
- Prior art keywords
- radical
- compound
- formula
- group
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- -1 Sulfonyl fluoride compound Chemical class 0.000 title claims abstract description 169
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 229940124530 sulfonamide Drugs 0.000 title claims abstract description 17
- 238000000034 method Methods 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 69
- 150000001875 compounds Chemical class 0.000 claims description 148
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 45
- 229910052794 bromium Inorganic materials 0.000 claims description 42
- 229910052801 chlorine Inorganic materials 0.000 claims description 42
- 229910052740 iodine Inorganic materials 0.000 claims description 40
- 229910052731 fluorine Inorganic materials 0.000 claims description 36
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 34
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 32
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 30
- 125000001424 substituent group Chemical group 0.000 claims description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 23
- 125000000623 heterocyclic group Chemical group 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 239000001257 hydrogen Substances 0.000 claims description 22
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 21
- 125000002950 monocyclic group Chemical group 0.000 claims description 19
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 18
- 125000002619 bicyclic group Chemical group 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 239000002585 base Substances 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 125000005842 heteroatom Chemical group 0.000 claims description 13
- 239000000654 additive Substances 0.000 claims description 12
- 230000000996 additive effect Effects 0.000 claims description 12
- 125000003368 amide group Chemical group 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 11
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 10
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 10
- 150000003254 radicals Chemical class 0.000 claims description 10
- KWEKXPWNFQBJAY-UHFFFAOYSA-N (dimethyl-$l^{3}-silanyl)oxy-dimethylsilicon Chemical compound C[Si](C)O[Si](C)C KWEKXPWNFQBJAY-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 125000005626 carbonium group Chemical group 0.000 claims description 8
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 6
- 229910004057 NO2F Inorganic materials 0.000 claims description 6
- 125000004423 acyloxy group Chemical group 0.000 claims description 6
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 6
- 238000005859 coupling reaction Methods 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 125000004185 ester group Chemical group 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000000018 nitroso group Chemical group N(=O)* 0.000 claims description 6
- JVJQPDTXIALXOG-UHFFFAOYSA-N nitryl fluoride Chemical compound [O-][N+](F)=O JVJQPDTXIALXOG-UHFFFAOYSA-N 0.000 claims description 6
- XSXHWVKGUXMUQE-UHFFFAOYSA-N osmium dioxide Inorganic materials O=[Os]=O XSXHWVKGUXMUQE-UHFFFAOYSA-N 0.000 claims description 6
- 125000005031 thiocyano group Chemical group S(C#N)* 0.000 claims description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 5
- GAURFLBIDLSLQU-UHFFFAOYSA-N diethoxy(methyl)silicon Chemical compound CCO[Si](C)OCC GAURFLBIDLSLQU-UHFFFAOYSA-N 0.000 claims description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 230000008878 coupling Effects 0.000 claims description 4
- 238000010168 coupling process Methods 0.000 claims description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 239000002798 polar solvent Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 125000006413 ring segment Chemical group 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 150000001340 alkali metals Chemical class 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- 229910017604 nitric acid Inorganic materials 0.000 claims description 3
- YQHJFPFNGVDEDT-UHFFFAOYSA-N 2-tert-butyl-1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(N(C)C)=NC(C)(C)C YQHJFPFNGVDEDT-UHFFFAOYSA-N 0.000 claims description 2
- VSCBATMPTLKTOV-UHFFFAOYSA-N 2-tert-butylimino-n,n-diethyl-1,3-dimethyl-1,3,2$l^{5}-diazaphosphinan-2-amine Chemical compound CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C VSCBATMPTLKTOV-UHFFFAOYSA-N 0.000 claims description 2
- FVKFHMNJTHKMRX-UHFFFAOYSA-N 3,4,6,7,8,9-hexahydro-2H-pyrimido[1,2-a]pyrimidine Chemical compound C1CCN2CCCNC2=N1 FVKFHMNJTHKMRX-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 150000001336 alkenes Chemical class 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- RGHILYZRVFRRNK-UHFFFAOYSA-N anthracene-1,2-dione Chemical group C1=CC=C2C=C(C(C(=O)C=C3)=O)C3=CC2=C1 RGHILYZRVFRRNK-UHFFFAOYSA-N 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 150000004649 carbonic acid derivatives Chemical group 0.000 claims description 2
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical class [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 claims description 2
- 239000000499 gel Substances 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000004678 hydrides Chemical class 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- AOTOAIFCUZOGTP-UHFFFAOYSA-N n-ethyl-2,3,4-trimethylpentan-3-amine Chemical compound CCNC(C)(C(C)C)C(C)C AOTOAIFCUZOGTP-UHFFFAOYSA-N 0.000 claims description 2
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims description 2
- 235000021317 phosphate Nutrition 0.000 claims description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 229910052703 rhodium Inorganic materials 0.000 claims description 2
- 229910000077 silane Inorganic materials 0.000 claims description 2
- 150000004756 silanes Chemical class 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 claims description 2
- 239000002210 silicon-based material Substances 0.000 claims description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 2
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 9
- 239000003513 alkali Substances 0.000 claims 4
- 125000005843 halogen group Chemical group 0.000 claims 1
- JOOXLOJCABQBSG-UHFFFAOYSA-N N-tert-butyl-3-[[5-methyl-2-[4-[2-(1-pyrrolidinyl)ethoxy]anilino]-4-pyrimidinyl]amino]benzenesulfonamide Chemical compound N1=C(NC=2C=C(C=CC=2)S(=O)(=O)NC(C)(C)C)C(C)=CN=C1NC(C=C1)=CC=C1OCCN1CCCC1 JOOXLOJCABQBSG-UHFFFAOYSA-N 0.000 abstract description 6
- 229950003487 fedratinib Drugs 0.000 abstract description 5
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 239000000047 product Substances 0.000 abstract description 3
- 150000003456 sulfonamides Chemical class 0.000 abstract description 3
- 239000006227 byproduct Substances 0.000 abstract description 2
- 238000000746 purification Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 238000012216 screening Methods 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 description 36
- 238000003786 synthesis reaction Methods 0.000 description 36
- 238000001514 detection method Methods 0.000 description 24
- IDIPWEYIBKUDNY-UHFFFAOYSA-N benzenesulfonyl fluoride Chemical compound FS(=O)(=O)C1=CC=CC=C1 IDIPWEYIBKUDNY-UHFFFAOYSA-N 0.000 description 22
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 10
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 10
- PLSYVJDMJWGODG-UHFFFAOYSA-N 3-aminobenzenesulfonyl fluoride Chemical compound NC1=CC=CC(S(F)(=O)=O)=C1 PLSYVJDMJWGODG-UHFFFAOYSA-N 0.000 description 9
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 7
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 125000003367 polycyclic group Chemical group 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 6
- 239000007787 solid Substances 0.000 description 4
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000001072 heteroaryl group Chemical group 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 3
- 125000003003 spiro group Chemical group 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- KDFDOINBXBEOLZ-UHFFFAOYSA-N 2-phenylpropan-2-amine Chemical compound CC(C)(N)C1=CC=CC=C1 KDFDOINBXBEOLZ-UHFFFAOYSA-N 0.000 description 2
- CUYKNJBYIJFRCU-UHFFFAOYSA-N 3-aminopyridine Chemical compound NC1=CC=CN=C1 CUYKNJBYIJFRCU-UHFFFAOYSA-N 0.000 description 2
- OTYZNDKWNPQQJP-UHFFFAOYSA-N 4-(2-pyrrolidin-1-ylethoxy)aniline Chemical compound C1=CC(N)=CC=C1OCCN1CCCC1 OTYZNDKWNPQQJP-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- 206010028537 myelofibrosis Diseases 0.000 description 2
- 239000012038 nucleophile Substances 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- PONXTPCRRASWKW-KWCCSABGSA-N (1r)-1,2-diphenylethane-1,2-diamine Chemical compound C1([C@@H](N)C(N)C=2C=CC=CC=2)=CC=CC=C1 PONXTPCRRASWKW-KWCCSABGSA-N 0.000 description 1
- OGNSDRMLWYNUED-UHFFFAOYSA-N 1-cyclohexyl-4-[4-[4-(4-cyclohexylcyclohexyl)cyclohexyl]cyclohexyl]cyclohexane Chemical group C1CCCCC1C1CCC(C2CCC(CC2)C2CCC(CC2)C2CCC(CC2)C2CCCCC2)CC1 OGNSDRMLWYNUED-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- IDRUEHMBFUJKAK-UHFFFAOYSA-N 2,4-dichloro-5-(trifluoromethyl)pyrimidine Chemical compound FC(F)(F)C1=CN=C(Cl)N=C1Cl IDRUEHMBFUJKAK-UHFFFAOYSA-N 0.000 description 1
- WHPFEQUEHBULBW-UHFFFAOYSA-N 2,4-dichloro-5-fluoropyrimidine Chemical compound FC1=CN=C(Cl)N=C1Cl WHPFEQUEHBULBW-UHFFFAOYSA-N 0.000 description 1
- DQXNTSXKIUZJJS-UHFFFAOYSA-N 2,4-dichloro-5-methylpyrimidine Chemical compound CC1=CN=C(Cl)N=C1Cl DQXNTSXKIUZJJS-UHFFFAOYSA-N 0.000 description 1
- INUSQTPGSHFGHM-UHFFFAOYSA-N 2,4-dichloro-5-nitropyrimidine Chemical compound [O-][N+](=O)C1=CN=C(Cl)N=C1Cl INUSQTPGSHFGHM-UHFFFAOYSA-N 0.000 description 1
- BTTNYQZNBZNDOR-UHFFFAOYSA-N 2,4-dichloropyrimidine Chemical compound ClC1=CC=NC(Cl)=N1 BTTNYQZNBZNDOR-UHFFFAOYSA-N 0.000 description 1
- OBUGJYJQJWMOQO-UHFFFAOYSA-N 2,5-dichloro-3-nitropyridine Chemical compound [O-][N+](=O)C1=CC(Cl)=CN=C1Cl OBUGJYJQJWMOQO-UHFFFAOYSA-N 0.000 description 1
- UPWAAFFFSGQECJ-UHFFFAOYSA-N 2,6-dichloro-3-(trifluoromethyl)pyridine Chemical compound FC(F)(F)C1=CC=C(Cl)N=C1Cl UPWAAFFFSGQECJ-UHFFFAOYSA-N 0.000 description 1
- LSPMHHJCDSFAAY-UHFFFAOYSA-N 2,6-dichloro-4-methylpyridine-3-carbonitrile Chemical compound CC1=CC(Cl)=NC(Cl)=C1C#N LSPMHHJCDSFAAY-UHFFFAOYSA-N 0.000 description 1
- 125000004638 2-oxopiperazinyl group Chemical group O=C1N(CCNC1)* 0.000 description 1
- ZDBWYUOUYNQZBM-UHFFFAOYSA-N 3-(aminomethyl)aniline Chemical compound NCC1=CC=CC(N)=C1 ZDBWYUOUYNQZBM-UHFFFAOYSA-N 0.000 description 1
- ZAJAQTYSTDTMCU-UHFFFAOYSA-N 3-aminobenzenesulfonic acid Chemical compound NC1=CC=CC(S(O)(=O)=O)=C1 ZAJAQTYSTDTMCU-UHFFFAOYSA-N 0.000 description 1
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 description 1
- TZCYLJGNWDVJRA-UHFFFAOYSA-N 6-chloro-1-hydroxybenzotriazole Chemical group C1=C(Cl)C=C2N(O)N=NC2=C1 TZCYLJGNWDVJRA-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 208000032027 Essential Thrombocythemia Diseases 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 101000844245 Homo sapiens Non-receptor tyrosine-protein kinase TYK2 Proteins 0.000 description 1
- 101000997835 Homo sapiens Tyrosine-protein kinase JAK1 Proteins 0.000 description 1
- 101000997832 Homo sapiens Tyrosine-protein kinase JAK2 Proteins 0.000 description 1
- 101000934996 Homo sapiens Tyrosine-protein kinase JAK3 Proteins 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
- 229940121730 Janus kinase 2 inhibitor Drugs 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 102100032028 Non-receptor tyrosine-protein kinase TYK2 Human genes 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 102100033438 Tyrosine-protein kinase JAK1 Human genes 0.000 description 1
- 102100033444 Tyrosine-protein kinase JAK2 Human genes 0.000 description 1
- 102100025387 Tyrosine-protein kinase JAK3 Human genes 0.000 description 1
- 208000017733 acquired polycythemia vera Diseases 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- MJBWDEQAUQTVKK-IAGOWNOFSA-N aflatoxin M1 Chemical compound C=1([C@]2(O)C=CO[C@@H]2OC=1C=C(C1=2)OC)C=2OC(=O)C2=C1CCC2=O MJBWDEQAUQTVKK-IAGOWNOFSA-N 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 229940125708 antidiabetic agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- MFZUXRKTKZKWSS-UHFFFAOYSA-N benzene;sulfuryl dichloride Chemical class ClS(Cl)(=O)=O.C1=CC=CC=C1 MFZUXRKTKZKWSS-UHFFFAOYSA-N 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- ZDZHCHYQNPQSGG-UHFFFAOYSA-N binaphthyl group Chemical group C1(=CC=CC2=CC=CC=C12)C1=CC=CC2=CC=CC=C12 ZDZHCHYQNPQSGG-UHFFFAOYSA-N 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- CRQQGFGUEAVUIL-UHFFFAOYSA-N chlorothalonil Chemical compound ClC1=C(Cl)C(C#N)=C(Cl)C(C#N)=C1Cl CRQQGFGUEAVUIL-UHFFFAOYSA-N 0.000 description 1
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000003336 coronenyl group Chemical group C1(=CC2=CC=C3C=CC4=CC=C5C=CC6=CC=C1C1=C6C5=C4C3=C21)* 0.000 description 1
- 125000000332 coumarinyl group Chemical group O1C(=O)C(=CC2=CC=CC=C12)* 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000004652 decahydroisoquinolinyl group Chemical group C1(NCCC2CCCCC12)* 0.000 description 1
- 125000005045 dihydroisoquinolinyl group Chemical group C1(NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000005044 dihydroquinolinyl group Chemical group N1(CC=CC2=CC=CC=C12)* 0.000 description 1
- 125000005879 dioxolanyl group Chemical group 0.000 description 1
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical compound CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- SRJBDGLSCPDXBL-UHFFFAOYSA-N ethyl 2,4-dichloropyrimidine-5-carboxylate Chemical compound CCOC(=O)C1=CN=C(Cl)N=C1Cl SRJBDGLSCPDXBL-UHFFFAOYSA-N 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000002192 heptalenyl group Chemical group 0.000 description 1
- 125000001633 hexacenyl group Chemical group C1(=CC=CC2=CC3=CC4=CC5=CC6=CC=CC=C6C=C5C=C4C=C3C=C12)* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000005945 imidazopyridyl group Chemical group 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 229940045996 isethionic acid Drugs 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000003384 isochromanyl group Chemical group C1(OCCC2=CC=CC=C12)* 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001298 n-hexoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- FFUBXANSXRGVKW-UHFFFAOYSA-N n-tert-butylbenzenesulfonamide Chemical compound CC(C)(C)NS(=O)(=O)C1=CC=CC=C1 FFUBXANSXRGVKW-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 125000005060 octahydroindolyl group Chemical group N1(CCC2CCCCC12)* 0.000 description 1
- 125000005061 octahydroisoindolyl group Chemical group C1(NCC2CCCCC12)* 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229940000673 orphan drug Drugs 0.000 description 1
- 239000002859 orphan drug Substances 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 1
- 125000003933 pentacenyl group Chemical group C1(=CC=CC2=CC3=CC4=CC5=CC=CC=C5C=C4C=C3C=C12)* 0.000 description 1
- 125000002080 perylenyl group Chemical group C1(=CC=C2C=CC=C3C4=CC=CC5=CC=CC(C1=C23)=C45)* 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 229940117803 phenethylamine Drugs 0.000 description 1
- NIXKBAZVOQAHGC-UHFFFAOYSA-N phenylmethanesulfonic acid Chemical compound OS(=O)(=O)CC1=CC=CC=C1 NIXKBAZVOQAHGC-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 208000037244 polycythemia vera Diseases 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 208000003476 primary myelofibrosis Diseases 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000001725 pyrenyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004590 pyridopyridyl group Chemical group N1=C(C=CC2=C1C=CC=N2)* 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical compound NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- OBTWBSRJZRCYQV-UHFFFAOYSA-N sulfuryl difluoride Chemical compound FS(F)(=O)=O OBTWBSRJZRCYQV-UHFFFAOYSA-N 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001935 tetracenyl group Chemical group C1(=CC=CC2=CC3=CC4=CC=CC=C4C=C3C=C12)* 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000003960 triphenylenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C3=CC=CC=C3C12)* 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/78—Halides of sulfonic acids
- C07C309/86—Halides of sulfonic acids having halosulfonyl groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/88—Halides of sulfonic acids having halosulfonyl groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a novel method for preparing sulfonamide compounds, in particular Fedratinib, and provides a novel intermediate and a preparation method of the intermediate. The preparation method disclosed by the invention is simple and safe to operate, does not need special purification equipment, can obtain reagents and raw materials for reaction in a commercially available manner, is mild in reaction condition, environment-friendly and pollution-free, high in product yield, high in purity and few in byproducts, can be used for quickly preparing different types of sulfonamides, and provides a brand-new method for quickly screening active sulfonamide compounds in medicinal chemistry.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a sulfonyl fluoride compound, a preparation method thereof and a novel method for preparing a sulfonamide compound from the sulfonyl fluoride compound.
Background
Due to the special biological activity of sulfonamide compounds, the sulfonamide compounds are receiving more and more attention from researchers, and are widely applied to medicines and pesticides, such as antibacterial agents, anticancer agents, antidiabetic agents, anti-AIDS agents, insecticides, and the like. Different sulfonamides in the medicine act on different targets to generate different biological activities, and the biological activities need to be rapidly screened in batches in the research and development of new medicines, so that the later functionalization of the medicines and the rapid preparation of series sulfonamide compounds are particularly important.
The sulfonamide drug Fedratinib (N-tert-butyl-3- [ (5-methyl-2- { [4- (2-pyrrolidin-1-ylethoxy) phenyl ] amino } pyrimidin-4-yl) amino ] benzenesulfonamide) is a high-selectivity JAK2 inhibitor, compared with family members JAK1, JAK3 and TYK2, it has higher inhibitory effect on JAK2, is entitled by FDA to orphan drug for treating secondary and primary myelofibrosis, is applied to market by New base company, is approved to market by US food and drug administration in 8 months of 2019, is used for treating primary or secondary (after polycythemia vera or after primary thrombocythemia) myelofibrosis adult patients at medium-risk-2 or high-risk, and provides a new once-a-day oral treatment option for the patients.
The currently reported preparation method of Fedratinib is mainly a related synthesis method reported in WO2012061833A1, US8133900B2 and the like. Specifically, benzene sulfonyl chloride compounds and tert-butylamine are adopted to generate sulfonamide compounds, then benzene sulfonyl tert-butylamine intermediates are synthesized through a route A and a route B, and the benzene sulfonyl tert-butylamine intermediates are further reacted with aniline compounds to obtain final products.
In the prior art, a benzenesulfonyl tert-butylamine intermediate needs to be prepared firstly, and then the intermediate is subjected to microwave or heating to obtain a final product, or a reactant is acidified and then alkalized and then reacts with the intermediate to obtain the final product. In the prior art, when different amines are used for replacing tert-butylamine to prepare Fedratinib analogues, different A or B type intermediates need to be prepared again, the steps are long, the process is complicated, and the efficiency is low. Therefore, there is a need to find a simple and efficient method that can modify the structure of the amine on the sulfonamide functionality at a later stage.
Disclosure of Invention
The invention provides a sulfonyl fluoride compound, a preparation method thereof and application of the sulfonyl fluoride compound in preparation of sulfonamide compounds. The inventor creatively provides a novel synthesis strategy for rapidly preparing sulfonamide compounds through sulfonyl fluoride intermediates. This strategy is particularly effective for the synthesis of Fedratinib and its analogs. This synthesis strategy constructs a compound of formula 4 by efficiently coupling a compound of formula 2 with a compound of formula 3, then constructs a compound of formula 6 by nucleophilic substitution or coupling a compound of formula 4 with a compound of formula 5, and finally constructs Fedratinib and its analogs from a compound of formula 6 and a compound of formula 7 by nucleophilic substitution. By adopting the synthesis strategy, different kinds of sulfonamide compounds can be rapidly prepared.
In a first aspect, the present invention provides a compound of formula (4) or a salt thereof:
wherein X is F, Cl, Br or I, Z is H, C1-C10Alkyl radical, C1-C10Alkoxy, F, Cl, Br, I, CN, NO2、CF3Or C2-C10Ester group, G1、G2、G3、G4、G5Is N or CR ', wherein R' is selected from H, C1-C10Alkyl radical, C1-C10Alkoxy, CN, CF3、C2-C10Ester group, NO2F, Cl, Br or I, and G1To G5At least one of which is not N; y is F, Cl, Br, I, C1-C10Alkyl radical, C1-C10Alkoxy, CN, NO2、CF3Amino or C2-C10An ester group, and n is 0, 1,2, 3 or 4.
Preferably, in the formula (4)Wherein X is F, Cl or Br, Z is H, C1-C6Alkyl radical, C1-C6Alkoxy, F, Cl, Br, I, CN, NO2、CF3Or C2-C6Ester group, G1、G2、G3、G4、G5Is N or CR ', wherein R' is selected from H, C1-C6Alkyl radical, C1-C6Alkoxy, CN, CF3、C2-C6Ester group, NO2F, Cl, Br or I, and G1To G5At least two of which are not N; y is F, Cl, Br, I, C1-C6Alkyl radical, C1-C6Alkoxy, CN, NO2、CF3Amino or C2-C6An ester group, and n is 0, 1,2, 3 or 4.
Further preferably, the compound of formula (4) is selected from:
in a second aspect, the present invention provides a process for the preparation of a compound of formula (4), which comprises reacting a compound of formula (2) with a compound of formula (3) via a nucleophilic substitution or coupling reaction to give a compound of formula (4):
wherein, X, Z, G1、G2、G3、G4、G5Y and n are as defined for formula (4).
Preferably, the compound of formula (2) is reacted with the compound of formula (3) in the presence of an organic solvent.
In one embodiment, the organic solvent is preferably a polar solvent, more preferably selected from any one of or any combination of water, methanol, ethanol, isopropanol, dimethylsulfoxide, N-dimethylformamide, N-dimethylacetamide or N-methylpyrrolidone, and even more preferably methanol/water.
In one embodiment, the amount of organic solvent used is 1 to 10mL relative to 1mmol of the compound of formula (2).
In one embodiment, the amount of the compound of formula (3) used is 1 to 10 equivalents with respect to 1 equivalent of the compound of formula (2).
According to the present invention, the reaction time is different for different compounds of formula (2) and different compounds of formula (3), and there is no particular limitation as long as the reaction can be completed. For example, the reaction time may be at least 1 hour, at least 2 hours, 12-48 hours, or 15-36 hours.
According to the present invention, the reaction temperature is different for different compounds of formula (2) and different compounds of formula (3), and there is no particular limitation as long as the reaction can be completed. For example, the reaction temperature may be 20 to 100 ℃, 30 to 70 ℃, 35 to 60 ℃ or 40 to 50 ℃.
In a third aspect, the present invention provides a compound of formula (6) or a salt thereof:
wherein R is10And R11The same or different, each independently selected from hydrogen and C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, above C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, optionally unsubstituted or substituted by one or moreEach substituent being independently selected from the group consisting of C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, amino, hydroxyl, mercapto, carboxyl, C1-C6Alkoxy radical, C3-C18Cycloalkoxy, C6-C20Halogenated aryl, C2-C6Alkoxycarbonyl, acyloxy, amido, ureido, C1-C6Alkylsulfonyl radical, C6-C20Arylsulfonyl radical, C1-C6Haloalkyl, F, Cl, Br, I, cyano, nitro, nitroso, thiocyano, isothiocyanato, C1-C6Sulfanyl, C1-C6Sulfoalkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl as a substituent alone or in free combination with the proviso that when R is10Or R11Any one of which is ethyl, butyl, trifluoroethyl, When the other is not H; or R10And R11Together with the N atom to which they are attached, form a heterocyclic group which is monocyclic, bicyclic or tricyclic, or which is a fused, bridged or spirocyclic ring, which heterocyclic group contains only one N atom or optionally in addition to the above-mentioned N atoms 1 or 2 or 3 heteroatoms selected from N, S and O, which heterocyclic group is unsubstituted or optionally substituted by one or more substituents each independently selected from the group consisting of C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, amino, hydroxyl, mercapto, carboxyl, C1-C6Alkoxy radical, C3-C8Cycloalkoxy, C2-C6Alkoxycarbonyl, F, Cl, Br, I, cyano, nitro, nitroso, amido, thiocyano, isothiocyanato, ureido, sulfo, alone or in combination; z is H, C1-C6Alkyl radical, C1-C6Alkoxy, F, Cl, Br, I, CN, NO2、CF3Or C2-C6Ester group with the proviso that when R10And R11And when H is the same, Z is not CN; g1、G2、G3、G4、G5Is N or CR ', wherein R' is selected from H, C1-C6Alkyl radical, C1-C6Alkoxy, CN, CF3、C2-C6Ester group, NO2F, Cl, Br or I, and G1To G5At least one of which is not N; y is F, Cl, Br, I, C1-C6Alkyl radical, C1-C6Alkoxy, CN, NO2、CF3Amino or C2-C6An ester group, and n is 0, 1,2, 3 or 4.
Preferably, in the compound of formula (6), R10And R11Independently selected from hydrogen, C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, above C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, optionally unsubstituted or substituted with one or more substituents each independently selected from the group consisting of1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, amino, hydroxyl, mercapto, carboxyl, C1-C6Alkoxy radical, C3-C18Cycloalkoxy, C2-C6Alkoxycarbonyl, acyloxy, amido, ureido, C1-C6Alkylsulfonyl radical, C6-C20Arylsulfonyl, F, Cl, Br, I, cyano, nitro, nitroso, thiocyano, isothiocyanato, C1-C6Sulfanyl, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl as a substituent alone or in free combination with the proviso that when R is10Or R11Any one of them is C1-C4Alkyl radical, C1-C2Haloalkyl, C substituted by hydroxy1-C6Alkyl, or anthracenedione substituted with amino, 4-sulfonylfluoroaniline, the other is not H; or R10And R11Together with the N atom to which they are attached, form a heterocyclic group which is monocyclic, bicyclic or tricyclic, or which is a fused, bridged or spirocyclic ring, which heterocyclic group contains only one N atom or optionally in addition to the above-mentioned N atoms 1 or 2 or 3 heteroatoms selected from N, S and O, which heterocyclic group is unsubstituted or optionally substituted by one or more substituents each independently selected from the group consisting of C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, amino, hydroxyl, mercapto, carboxyl, C1-C6Alkoxy radical, C3-C8Cycloalkoxy, C2-C6Alkoxycarbonyl, F, Cl, Br, I, cyano, nitro, nitroso, amido, thiocyano, isothiocyanato, ureido, sulfo, alone or in combination; g1To G5At least two of which are not N.
Further preferably, the compound of formula (6) is selected from:
in a fourth aspect, the present invention provides a process for the preparation of a compound of formula (6), which comprises subjecting a compound of formula (4) to nucleophilic substitution or coupling reaction with a compound of formula (5) to give a compound of formula (6):
wherein X is F, Cl, Br or I, G1、G2、G3、G4、G5、Y、n、Z、R10And R11Is as defined in formula (6).
Preferably, the compound of formula (4) is reacted with the compound of formula (5) in the presence of an organic solvent and an acid.
In one embodiment, the organic solvent is preferably a polar solvent, more preferably selected from methanol, ethanol, isopropanol, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide or N-methylpyrrolidone.
In one embodiment, the organic solvent is used in an amount of 1 to 10mL with respect to 1mmol of the compound of formula (4).
In one embodiment, the acid is preferably concentrated hydrochloric acid, concentrated phosphoric acid, concentrated sulfuric acid or concentrated nitric acid, more preferably concentrated hydrochloric acid or concentrated phosphoric acid. In one embodiment, the acid is used in an amount of 1 to 10 equivalents with respect to 1 equivalent of the compound of formula (4).
In one embodiment, the compound of formula (5) is used in an amount of 1 to 10 equivalents with respect to 1 equivalent of the compound of formula (4).
According to the present invention, the reaction time is different for different compounds of formula (4) and different compounds of formula (5), and there is no particular limitation as long as the reaction can be completed. For example, the reaction time may be at least 1 hour, at least 2 hours, 9-48 hours, or 15-36 hours.
According to the present invention, the reaction temperature is different for different compounds of formula (4) and different compounds of formula (5), and there is no particular limitation as long as the reaction can be completed. For example, the reaction temperature may be 40-100 ℃, 50-90 ℃, 60-80 ℃ or 70 ℃.
In a fifth aspect, the present invention provides the use of a compound of formula (4) and a compound of formula (6) or a salt thereof in the preparation of a sulfonamide compound.
In a sixth aspect, the present invention provides a process for the preparation of a compound of formula (1), which comprises subjecting a compound of formula (6) and a compound of formula (7) to a nucleophilic substitution reaction to obtain a compound of formula (1), the reaction being carried out in the presence of a catalyst and optionally an additive or optionally a base:
wherein R is1And R2The same or different, each independently selected from hydrogen and C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, above C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, optionally unsubstituted or substituted with one or more substituents each independently selected from the group consisting of1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, amino, hydroxyl, mercapto, carboxyl, C1-C6Alkoxy radical, C3-C18Cycloalkoxy, C6-C20Halogenated aryl, C2-C6Alkoxycarbonyl, acyloxy, amido, ureido, C1-C6Alkylsulfonyl radical, C6-C20Arylsulfonyl radical, C1-C6Haloalkyl, F, Cl, Br, I, cyano, nitro, nitroso, thiocyano, isothiocyanato, C1-C6Sulfanyl, C1-C6Sulfoalkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl is taken as a substituent independently or is formed by free combination; or R10And R11Together with the N atom to which they are attached, form a heterocyclic group which is monocyclic, bicyclic or tricyclic, or which is a fused, bridged or spirocyclic ring, which heterocyclic group contains only one N atom or optionally in addition to the above-mentioned N atoms 1 or 2 or 3 heteroatoms selected from N, S and O, which heterocyclic group is unsubstituted or optionally substituted by one or more substituents each independently selected from the group consisting of C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, amino, hydroxyl, mercapto, carboxyl, C1-C6Alkoxy radical, C3-C8Cycloalkoxy, C2-C6Alkoxycarbonyl, F, Cl, Br, I, cyano, nitro, nitroso, amido, thiocyano, isothiocyanato, ureido, sulfo, alone or in combination; g1、G2、G3、G4、G5、Y、n、Z、R10And R11Is as defined in formula (6).
In one embodiment, the catalyst is a compound of formula (I) or a compound of formula (II), or a combination thereof:
in the formulae (I) and (II), R1And R2Are each independently of the others selected from hydrogen, hydroxy, F, Cl, Br, I, C1-C6Alkyl radical, NO2、C1-C6Alkoxy, amino, C1-C6Alkyl monosubstituted amino, C1-C6Alkyl-disubstituted amino, C1-C6Haloalkyl, C1-C6An alkyloxycarbonyl group; or R1And R2Together with the carbon atom to which they are attached form ring a;
the ring A is selected from: a monocyclic or compensated bicyclic aromatic ring having 6-10 carbon atoms; a monocyclic or compensated bicyclic heteroaryl ring having 5-10 ring atoms comprising 1-3 heteroatoms selected from N, O, S and any combination thereof; a monocyclic or fused bicyclic carbocycle having 3-10 carbon atoms; a monocyclic or compensated bicyclic heterocycle having 3-10 ring atoms comprising 1-3 heteroatoms selected from N, O, S and any combination thereof;
said ring A being optionally substituted by one or more than one substituent RaSubstituted, each substituent RaIdentical or different, independently of one another, from the group consisting of hydroxyl, F, Cl, Br, I, C1-C18Alkyl radical, NO2、C1-C18Alkoxy, amino, C1-C6Alkyl monosubstituted amino, C1-C6Alkyl-disubstituted amino, C1-C6Haloalkyl, C1-C6Alkyl oxycarbonyl radical, C6-C10Aryl, benzyl;
R3are respectively selected from hydrogen, hydroxyl, sulfydryl, F, Cl, Br, I and C1-C6Alkyl radical, NO2、C1-C6Alkoxy, amino, C1-C6Alkyl monosubstituted amino, C1-C6Alkyl-disubstituted amino, C1-C6Haloalkyl, C1-C18Alkyloxycarbonyl, oxytris (pyrrolidinyl) phosphonium hexafluorophosphate, oxytris (pyrrolidinyl) phosphonium tetrafluoroborate, oxytris (dimethylamino) phosphonium hexafluorophosphate, oxytris (dimethylamino) phosphonium tetrafluoroborate, oxydi (dimethylamino) carbonium hexafluorophosphate, oxydi (dimethylamino) carbonium tetrafluoroborate, oxydi (pyrrolidinyl) carbonium hexafluorophosphate, oxydi (pyrrolidinyl) carbonium tetrafluoroborate, -OSO2C1-C6Alkyl, -OSO2C1-C8Perfluoroalkyl group, -OSO2C6-C10And (4) an aryl group.
According to the present invention, the activity of the catalyst is related to the substituents but is not particularly sensitive, so that the substituents are not particularly limited and can catalyze the reaction to some extent with respect to compounds having the same parent structure.
In one embodiment, the catalyst is selected from any one of the following compounds, or any combination thereof:
In one embodiment, the catalyst is used in an amount of 0.0001 to 2.0 equivalents with respect to 1 equivalent of the compound of formula (6).
In one embodiment, the additive is a silicon-containing compound selected from the group consisting of:
unsubstituted or substituted trimethylsilyl, C1-C4Alkyl radical, C1-C4Haloalkyl, phenyl, C1-C4Alkoxy or any combination thereof mono-or poly-substituted silane;
unsubstituted or by C1-C4Alkyl radical, C1-C4Haloalkyl, phenyl, C1-C4Alkoxy or any combination thereof mono-or poly-substituted disiloxane;
a compound of formula (III)Wherein the substituent Re、Rf、Rg、Rh、Ri、Rj、RkIdentical or different, independently of one another, from hydrogen, C1-C4Alkyl radical, C1-C4Haloalkyl, phenyl, C1-C4An alkoxy group;
a compound of formula (IV)Wherein R isl、Rm、Rn、Ro、Rp、RqIdentical or different, independently of one another, from hydrogen, C1-C4Alkyl radical, C1-C4Haloalkyl, phenyl, C1-C4An alkoxy group;
a compound of formula (V)Wherein R isr、Rs、Rt、Ru、Rv、Rw、Rx、RyIdentical or different, independently of one another, from hydrogen, C1-C4Alkyl radical, C1-C4Haloalkyl, phenyl, C1-C4Alkoxy, n is 1-2000, preferably 10-1000, more preferably 100-500.
According to the present invention, the activity of the additive is related to the substituent but is not particularly sensitive as long as it satisfies the conditions of having a strong affinity for fluoride ions and being compatible with other substances in the reaction system, and the substituent is not particularly limited and can promote the reaction to some extent.
Preferably, the additive is selected from (TMS)2O, 1,1,3, 3-tetramethyldisiloxane, methyldiethoxysilane, silica gels, where n is 1-2000, preferably 10-1000, more preferably 100-500C3H9OSi·(CH4OSi)n·C3H9Si or any one or any combination of the following compounds:
in a preferred embodiment, the additive is selected from (TMS)2O, 1,3, 3-tetramethyldisiloxane, methyldiethoxysilane, or any combination thereof.
In one embodiment, the additive is used in an amount of 0 to 10 equivalents with respect to 1 equivalent of the compound of formula (6).
In one embodiment, the base is an organic or inorganic base selected from the group consisting of: r11R12NR13Wherein R is11、R12And R13Independently of one another, from hydrogen, C1-C4An alkyl group; r21R22N-Y-NR23R24Y is C1-C3Alkylene radical, R21、R22、R23And R24Independently of one another, from hydrogen, C1-C4An alkyl group; unsubstituted or substituted by halogen, C1-C4Alkyl-substituted diaza or triazabicyclo C6-C12An olefin;
the inorganic base is selected from carbonates, phosphates, hydrides and C of alkali metals or alkaline earth metals1-C18An alkyl oxide;
preferably, the base is selected from triethylamine, diisopropyldiethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5, 7-triazabicyclo [4.4.0] dec-5-ene (TBD), 1, 4-diazabicyclo [2.2.2] octane (DABCO), potassium carbonate, cesium carbonate, potassium phosphate, 2-tert-butylimino-2-diethylamino-1, 3-dimethylperhydro-1, 3, 2-diazaphosphorus (BEMP) and 2-tert-butyl-1, 1,3, 3-tetramethylguanidine (Barton base);
more preferably, the base is triethylamine or diisopropylethylamine.
In one embodiment, the base is used in an amount of 0 to 10 equivalents with respect to 1 equivalent of the compound of formula (6).
In one embodiment, the compound of formula (7) is used in an amount of 0.2 to 10 equivalents with respect to 1 equivalent of the compound of formula (6).
The nucleophilic substitution reaction can be carried out in the presence or absence of a solvent. In the case of using a solvent, the solvent is an organic solvent, and the kind and amount of the organic solvent are not particularly limited as long as the reactants, the catalyst, and the optional additive or the optional base can be partially dissolved.
In one embodiment, the solvent is selected from C1-C4Alcohol solutionAgent, C1-C4Nitrile solvent, C1-C4Halogenated hydrocarbon solvent, C6-C10Aromatic hydrocarbon solvent, C2-C4Sulfone solvent and C3-C6An amide solvent; preferably, the solvent is selected from methanol, ethanol, isopropanol, tert-butanol, acetonitrile, dichloromethane, toluene, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide or, N-methylpyrrolidone; more preferably, the solvent is dichloromethane, dimethyl sulfoxide, N-methylpyrrolidone or N, N-dimethylformamide. In one embodiment, the solvent is used in an amount of 1 to 10mL with respect to 1mmol of the compound of formula (6).
According to the present invention, the nucleophilic substitution reaction is carried out for different compounds of formula (6) and different nucleophiles at different reaction times, and there is no particular limitation as long as the reaction can be completed. For example, the reaction time may be at least 1 hour, at least 2 hours, 3 to 10 hours, or 3 to 7 hours.
According to the present invention, the nucleophilic substitution reaction is carried out for different compounds of formula (6) and different nucleophiles at different reaction temperatures, which are not particularly limited as long as the reaction can be completed. For example, the reaction temperature may be 20 to 100 ℃, 30 to 80 ℃, 30 to 50 ℃ or 30 to 40 ℃.
Compared with the prior art, the invention has the following advantages: the preparation method disclosed by the invention is simple and safe to operate, does not need special purification equipment, can obtain reagents and raw materials for reaction in a commercially available manner, is mild in reaction condition, environment-friendly, pollution-free, high in product yield, high in purity and few in byproducts, can quickly prepare different types of sulfamide, and provides a brand-new method for preparing series compounds in medicinal chemistry.
Detailed Description
The abbreviations used in the present invention are summarized in the following table:
TABLE 1
Definition of
The term "alkyl" as used herein refers to a group consisting of only carbon and hydrogen atoms, and having no unsaturation (e.g., double bonds, triple bonds, or rings), which encompasses a wide variety of possible geometric and stereoisomeric groups. This group is attached to the rest of the molecule by a single bond. By way of non-limiting examples of alkyl groups, mention may be made of the following linear or branched groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and seven further isomers thereof, n-hexyl and sixteen further isomers thereof, n-heptyl and respective isomers thereof, n-octyl and respective isomers thereof, n-nonyl and respective isomers thereof.
The term "cycloalkyl" as used herein refers to a saturated non-aromatic ring system of at least 3 carbon atoms which may be monocyclic, bicyclic, polycyclic, fused, bridged, or spiro. As non-limiting examples of cycloalkyl groups, the following groups may be cited: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl; and fused, bridged, or spiro ring groups formed from two or more of the above-described monocyclic rings via a common side and a common carbon atom.
The term "alkenyl" as used herein refers to a group formed in the presence of one or more double bonds (other than methyl) in the above alkyl group.
The term "alkynyl" as used herein refers to a group formed when one or more triple bonds (other than methyl) are present in the alkyl group described above.
The term "alkoxy" as used herein refers to a group having an oxygen atom attached to the alkyl group and a single bond through the oxygen atom to the rest of the molecule, and encompasses a wide variety of possible geometric and stereoisomeric groups. As non-limiting examples of alkoxy radicals, the following straight-chain or branched radicals may be cited: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy and further seven isomers, n-hexoxy and further sixteen isomers, n-heptoxy and various isomers, n-octoxy and various isomers, n-nonoxy and various isomers.
The term "aryl" as used herein refers to an aromatic ring system consisting of at least 6 carbon atoms, which may be monocyclic, bicyclic, polycyclic, wherein bicyclic and polycyclic rings may be formed from a single ring by single bond linkages or by fusion. As non-limiting examples of aryl groups, the following groups may be cited: phenyl, naphthyl, anthryl, phenanthryl, indenyl, pyrenyl, perylenyl, pentalenyl, heptalenyl, triphenylenyl, tetracenyl, pentalenyl, pentacenyl, tetrao-phenylene, hexaphenyl, hexacenyl, coronenyl, trinaphthyl, heptenyl, heptaphenyl, egg phenyl, biphenyl, binaphthyl.
The term "heteroaryl" as used herein refers to a 5-20 membered aromatic heterocyclic ring system having one or more heteroatoms independently selected from N, O or S, which may be monocyclic, bicyclic, polycyclic, wherein bicyclic and polycyclic rings may be formed from a single ring by single bond linkages or fused. As non-limiting examples of heteroaryl groups, the following groups may be cited: oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuryl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzofuryl, carbazolyl, isoquinolyl, quinazolinyl, naphthyridinyl, purinyl, thiadiazolyl, indolizinyl, phenazinyl, coumarinyl, pyridopyridyl, pyridopyridazinyl, imidazopyridyl, imidazopyridazinyl; and a group formed by the above-mentioned heteroaryl group by a single bond connection or a fusion connection.
The term "heterocyclyl" as used herein, means a non-aromatic 3-18 membered ring system consisting of carbon atoms and heteroatoms independently selected from N, O or S, which ring system may be monocyclic, bicyclic, or polycyclic, and may be fused, bridged, or spiro, and may optionally contain one or more double bonds. As non-limiting examples of heterocyclyl groups, the following groups may be mentioned: acridinyl, benzodioxacyclohexyl, benzopyranyl, chromanyl, dioxolanyl, decahydroisoquinolinyl, indanyl, indolinyl, isoindolinyl, isochromanyl, morpholinyl, piperazinyl, 2-oxopiperazinyl, octahydroindolyl, octahydroisoindolyl, 4-piperidinonyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, 1- (diphenylmethyl) piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, and combinations thereof.
The salt of the compound of formula (4) or the salt of the compound of formula (6) means a pharmaceutically acceptable salt and ordinary salts thereof, for example, a base addition salt with a carboxyl group when the compound has a carboxyl group, an acid addition salt with an amino group or a basic heterocyclic group when the compound has an amino group or a basic heterocyclic group, and the like.
The above base addition salts include those with alkali metals (e.g., sodium, potassium); alkaline earth metals (e.g., calcium, magnesium); ammonium or organic amines (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine), and the like.
The above-mentioned acid addition salts include salts with inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid), organic acids (e.g., maleic acid, fumaric acid, tartaric acid, citric acid, ascorbic acid, trifluoroacetic acid), sulfonic acids (methanesulfonic acid, isethionic acid, phenylmethanesulfonic acid, p-toluenesulfonic acid), and the like.
In the present invention, a numerical range covers any number within the range.
Reagents used in the present invention are commercially available unless otherwise specifically indicated.
Examples
The present invention is further illustrated by the following examples, but the present invention is not limited to these specific examples, and may be arbitrarily changed without departing from the spirit and scope of the present invention.
EXAMPLE 1 Synthesis of a Compound of formula 4 (3- (2-chloro-5-methylpyrimidin-4-amino) benzenesulfonyl fluoride)
To a reaction flask was added 3-aminobenzenesulfonyl fluoride (1.80g, 10.3mmol), 2, 4-dichloro-5-methylpyrimidine (2.00g, 1.2eq), methanol/water ═ 1:1(34mL), and the reaction was carried out at 45 ℃ for 24 hours. White solid is separated out in the reaction process, the reaction product is filtered, a filter cake is washed by methanol/water (1: 1), and the filter cake is dried to obtain the white solid with the yield of 88%. The detection result is as follows: ms (esi): 302.0(35Cl),303.9(37Cl)[M+H]+。
Example 2 Synthesis of Compound of formula 4 (3- ((2-Chloropyrimidin-4-yl) amino) benzenesulfonyl fluoride)
To a reaction flask were added 3-aminobenzenesulfonyl fluoride (35.0mg, 0.2mmol), 2, 4-dichloropyrimidine (35.8mg, 1.2eq), methanol/water ═ 1:1(0.66mL), and the mixture was reacted at 45 ℃ for 24 hours. The detection result is as follows: ms (esi): 286.0(35Cl),288.0(37Cl)[M-H]-。
EXAMPLE 3 Synthesis of Compound of formula 4 (3- ((2-chloro-5-fluoropyrimidin-4-yl) amino) benzenesulfonyl fluoride)
To a reaction flask were added 3-aminobenzenesulfonyl fluoride (35.0mg, 0.2mmol), 2, 4-dichloro-5-fluoropyrimidine (40.0mg, 1.2eq), methanol/water ═ 1:1(0.66mL), and reacted at 45 ℃ for 24 hours. The detection result is as follows: ms (esi): 304.0(35Cl),305.9(37Cl)[M-H]-。
EXAMPLE 4 Synthesis of Compound of formula 4 (3- ((2-chloro-5-nitropyrimidin-4-yl) amino) benzenesulfonyl fluoride)
Adding 3-aminobenzenesulfonic acid into a reaction bottleAcyl fluoride (35.0mg, 0.2mmol), 2, 4-dichloro-5-nitropyrimidine (46.6mg, 1.2eq), methanol/water ═ 1:1(0.66mL), and reacted at 45 ℃ for 24 hours. The detection result is as follows: ms (esi): 330.9(35Cl),332.9(37Cl)[M-H]-。
EXAMPLE 5 Synthesis of Compound of formula 4 (3- ((2-chloro-5-trifluoromethylpyrimidin-4-yl) amino) benzenesulfonyl fluoride)
To a reaction flask was added 3-aminobenzenesulfonyl fluoride (35.0mg, 0.2mmol), 2, 4-dichloro-5-trifluoromethylpyrimidine (52.1mg, 1.2eq), methanol/water ═ 1:1(0.66mL), and reacted at 45 ℃ for 24 hours. The detection result is as follows: ms (esi): 353.9(35Cl),355.9(37Cl)[M-H]-。
EXAMPLE 6 Synthesis of Compound of formula 4 (ethyl 2-chloro-4- ((3- (fluorosulfonyl) phenyl) amino) pyrimidine-5-carboxylate)
To a reaction flask were added 3-aminobenzenesulfonyl fluoride (35.0mg, 0.2mmol), ethyl 2, 4-dichloro-5-pyrimidinecarboxylate (53.0mg, 1.2eq), methanol/water ═ 1:1(0.66mL), and reacted at 45 ℃ for 24 hours. The detection result is as follows: ms (esi): 357.9(35Cl),359.9(37Cl)[M-H]-。
EXAMPLE 7 Synthesis of Compound of formula 4 (3- ((6-chloro-5-cyano-4-methylpyridin-2-yl) amino) benzenesulfonyl fluoride)
To a reaction flask was added 3-aminobenzenesulfonyl fluoride (35.0mg, 0.2mmol), 3-cyano-4-methyl-2, 6-dichloropyridine (44.9mg, 1.2eq), methanol/water ═ 1:1(0.66mL), and the reaction was carried out at 45 ℃ for 24 hours. The detection result is as follows: ms (esi): 324.0(35Cl),326.0(37Cl)[M-H]-。
EXAMPLE 8 Synthesis of Compound of formula 4 (3- ((6-chloro-5-nitropyridin-3-yl) amino) benzenesulfonyl fluoride)
To a reaction flask were added 3-aminobenzenesulfonyl fluoride (35.0mg, 0.2mmol), 2, 5-dichloro-3-nitropyridine (46.3mg, 1.2eq), methanol/water ═ 1:1(0.66mL), and the reaction was carried out at 45 ℃ for 24 hours. The detection result is as follows: ms (esi): 329.9(35Cl),331.9(37Cl)[M-H]-。
Example 9 Synthesis of Compound of formula 4 (3- ((6-chloro-5- (trifluoromethyl) pyridin-2-yl) amino) benzenesulfonyl fluoride)
To a reaction flask was added 3-aminobenzenesulfonyl fluoride (35.0mg, 0.2mmol), 2, 6-dichloro-3-trifluoromethylpyridine (51.8mg, 1.2eq), isopropanol/water ═ 1:1(0.66mL), and reacted at 85 ℃ for 24 hours. The detection result is as follows: ms (esi): 352.9(35Cl),354.9(37Cl)[M-H]-。
EXAMPLE 10 Synthesis of a Compound of formula 4 (3- ((2,3, 5-trichloro-4, 6-dicyanophenyl) amino) benzenesulfonyl fluoride)
3-Aminobenzenesulfonyl fluoride (35.0mg, 0.2mmol), tetrachloroisophthalonitrile (63.8mg, 1.2eq), and DMSO (1mL) were added to the reaction flask and reacted at 85 ℃ for 24 hours. The detection result is as follows: ms (esi): 401.8(335Cl),403.8(2 35Cl+37Cl)[M-H]-。
EXAMPLE 11 Synthesis of the Compound of formula 6 (3- (2- (4- (2- (pyrrolidinyl-1-yl) ethoxy) phenylamino) -5-methylpyrimidin-4-ylamino) benzenesulfonyl fluoride)
3- (2-chloro-5-methylpyrimidin-4-amino) benzenesulfonyl fluoride (1.10g, 3.6mmol), 4- (2-pyrrolidin-1-yl-ethoxy) -phenylamine (1.00g, 1.3eq), 14mL isopropanol were added to the reaction flask. Adding 2.0eq concentrated hydrochloric acid, reacting at 70 ℃ for 24 hours, starting monitoring, cooling to room temperature after the reaction is finished, performing suction filtration, washing with 10mL isopropanol, and drying to obtain an off-white solid with the yield of 95%. The detection result is as follows: ms (esi): 472.1[ M + H]+。
EXAMPLE 12 Synthesis of a Compound of formula 6 (3- (2- (4- (2- (pyrrolidinyl-1-yl) ethoxy) phenylamino) -5-methylpyrimidin-4-ylamino) benzenesulfonyl fluoride)
3- (2-chloro-5-methylpyrimidin-4-amino) benzenesulfonyl fluoride (100.0mg, 0.33mmol), 4- (2-pyrrolidin-1-yl-ethoxy) -phenylamine (88.0mg, 1.3eq), 1.2mL of dimethylsulfoxide was added to the reaction flask. 1.4eq of concentrated HCl was added and the reaction was carried out at 70 ℃ for 24 hours. HPLC purity of crude product: 97 percent.
EXAMPLE 13 Synthesis of a Compound of formula 6 (3- ((2- ((4-methoxyphenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonyl fluoride)
3- (2-chloro-5-methylpyrimidin-4-amino) benzenesulfonyl fluoride (30.2mg, 0.1mmol), p-anisidine (16.0mg, 1.3eq), 0.4mL of isopropanol were added to the reaction flask. 2.0eq of concentrated HCl was added and the reaction was carried out at 70 ℃ for 24 hours. The detection result is as follows: ms (esi): 387.0[ M-H ]]-。
EXAMPLE 14 Synthesis of Compound of formula 6 (3- ((2- ((4-fluorophenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonyl fluoride)
3- (2-chloro-5-methylpyrimidin-4-amino) benzenesulfonyl fluoride (30.2mg, 0.1mmol), p-fluoroaniline (14.0mg, 1.3eq), 0.4mL isopropanol were added to the reaction flask. 2.0eq of concentrated HCl was added and the reaction was carried out at 70 ℃ for 24 hours. The detection result is as follows: ms (esi): 375.0[ M-H ]]-。
EXAMPLE 15 Synthesis of Compound of formula 6 ((S) -3- ((2- (((1- (4-chlorophenyl) ethyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonyl fluoride)
3- (2-chloro-5-methylpyrimidin-4-amino) benzenesulfonyl fluoride (30.2mg, 0.1mmol), S-4-chlorophenylethylamine (20.3mg, 1.3eq), 0.4mL of isopropanol were added to the reaction flask. 2.0eq of concentrated HCl was added and the reaction was carried out at 70 ℃ for 24 hours. The detection result is as follows: ms (esi): 421.0(35Cl),422.9(37Cl)[M+H]+。
EXAMPLE 16 Synthesis of Compound of formula 6 (3- ((5-methyl-2- (pyridin-3-ylamino) pyrimidin-4-yl) amino) benzenesulfonyl fluoride)
3- (2-chloro-5-methylpyrimidin-4-amino) benzenesulfonyl fluoride (30.2mg, 0.1mmol), 3-aminopyridine (12.2mg, 1.3eq), 0.4mL isopropanol were added to the reaction flask. 2.0eq of concentrated HCl was added and the reaction was carried out at 70 ℃ for 24 hours. The detection result is as follows: ms (esi): 358.0[ M-H]-。
EXAMPLE 17 Synthesis of a Compound of formula 6 (3- ((5-methyl-2-morpholinopyrimidin-4-yl) amino) benzenesulfonyl fluoride)
3- (2-chloro-5-methylpyrimidin-4-amino) benzenesulfonyl fluoride (30.2mg, 0.1mmol), morpholine (11.0. mu.L, 1.3eq), 0.4mL of isofluranePropanol was added to the reaction flask. 2.0eq of concentrated HCl was added and the reaction was carried out at 70 ℃ for 24 hours. The detection result is as follows: ms (esi): 351.0[ M-H ]]-。
EXAMPLE 18 Synthesis of Compound of formula 6 (3- ((2- (((3s,5s,7s) -adamantan-1-yl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonyl fluoride)
3- (2-chloro-5-methylpyrimidin-4-amino) benzenesulfonyl fluoride (30.2mg, 0.1mmol), 1-adamantanamine (19.7mg, 1.3eq), 0.4mL isopropanol were added to the reaction flask. 2.0eq of concentrated HCl was added and the reaction was carried out at 70 ℃ for 24 hours. The detection result is as follows: ms (esi): 417.1[ M + H]+。
EXAMPLE 19 Synthesis of Compound of formula 6 (3- ((2- (((1R,2R) -2-amino-1, 2-diphenylethyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonyl fluoride)
3- (2-chloro-5-methylpyrimidin-4-amino) benzenesulfonyl fluoride (30.2mg, 0.1mmol), R, R-diphenylethylenediamine (27.6mg, 1.3eq), 0.4mL of isopropanol were added to the reaction flask. 2.0eq of concentrated HCl was added and the reaction was carried out at 70 ℃ for 24 hours. The detection result is as follows: ms (esi): 478.0[ M + H]+。
EXAMPLE 20 Synthesis of a Compound of formula 6 (3- ((2- (dipropylamino) -5-methylpyrimidin-4-yl) amino) benzenesulfonyl fluoride)
3- (2-chloro-5-methylpyrimidin-4-amino) benzenesulfonyl fluoride (30.2mg, 0.1mmol), di-n-propylamine (17.8. mu.L, 1.3eq), 0.4mL of isopropanol were added to the reaction flask. 2.0eq of concentrated HCl was added and the reaction was carried out at 70 ℃ for 24 hours. The detection result is as follows: ms (esi): 367.1[ M + H]+。
EXAMPLE 21 Synthesis of a Compound of formula 6 (3- ((2- (dipropylamino) -5-methylpyrimidin-4-yl) amino) benzenesulfonyl fluoride)
3- (2-chloro-5-methylpyrimidin-4-amino) benzenesulfonyl fluoride (30.2mg, 0.1mmol), 3-aminobenzylamine (15.9mg, 1.3eq), 0.4mL of isopropanol were added to the reaction flask. 2.0eq of concentrated HCl was added and the reaction was carried out at 70 ℃ for 24 hours. The detection result is as follows: ms (esi): 386.0[ M-H ]]-。
EXAMPLE 22 Synthesis of Compound of formula 6 (3- ((5-methyl-2- ((2-phenylpropan-2-yl) amino) pyrimidin-4-yl) amino) benzenesulfonyl fluoride)
3- (2-chloro-5-methylpyrimidin-4-amino) benzenesulfonyl fluoride (30.2mg, 0.1mmol), α, α -dimethylbenzylamine (17.6mg, 1.3eq), 0.4mL of isopropanol were added to the reaction flask. 2.0eq of concentrated HCl was added and the reaction was carried out at 70 ℃ for 24 hours. The detection result is as follows: ms (esi): 401.1[ M + H]+。
EXAMPLE 23 Synthesis of Compound of formula 1 (N-tert-butyl-3- ((5-methyl-2- ((4- (2-pyrrolidin-1-ylethoxy) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide)
To a reaction flask was added the compound of formula 6 (3- (2- (4- (2- (pyrrolidinyl-1-yl) ethoxy) phenylamino) -5-methylpyrimidin-4-ylamino) benzenesulfonyl fluoride) (0.12mmol, 1.2eq), 125. mu.L DMSO, 2.0eq N, N-diisopropylethylamine, tert-butylamine (10.5. mu.L, 1.0eq), 0.2eq HOBt, 2.0eq (TMS)2O, reacting at 60 ℃ for 24 hours. The nuclear magnetic calculation yield is 89%.
EXAMPLE 24 Synthesis of Compound of formula 1 (N-tert-butyl-3- ((5-methyl-2- ((4- (2-pyrrolidin-1-ylethoxy) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide)
A reaction flask was charged with the compound of formula 6 (3- (2- (4- (2- (pyrrolidinyl-1-yl) ethoxy) phenylamino) -5-methylpyrimidin-4-ylamino) benzenesulfonyl fluoride) (0.24mmol, 1.2eq), 250. mu.L of DMSO, tert-butylamine (21.0. mu.L, 0.2mmol, 1.0eq), 0.01eq of HOBt, 2.0eq of N, N-diisopropylethylamine, 2.0eq 1,1,3, 3-tetramethyldisiloxane), reacted at 25 ℃ for 24 hours, and after the reaction was completed, 70mL of chloroform was added, washed twice with water, dried over anhydrous sodium sulfate, concentrated to dryness to give an off-white solid in an isolated yield of 93%.
EXAMPLE 25 Synthesis of Compound of formula 1 (N-tert-butyl-3- ((5-methyl-2- ((4- (2-pyrrolidin-1-ylethoxy) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide)
The reaction was carried out in the same manner as in example 25 except that the temperature was increased to 60 ℃, and the nuclear magnetic calculated yield was 100%.
EXAMPLE 26 Synthesis of Compound of formula 1 (N-tert-butyl-3- ((5-methyl-2- ((4- (2-pyrrolidin-1-ylethoxy) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide)
The reaction was carried out in the same manner as in example 25 except that the amount of HOBt was changed to 0.001eq and the temperature was increased to 60 ℃, whereby the nuclear magnetic calculation yield was 100%.
EXAMPLE 27 Synthesis of Compound of formula 1 (N-tert-butyl-3- ((5-methyl-2- ((4- (2-pyrrolidin-1-ylethoxy) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide)
The reaction was carried out in the same manner as in example 25 except that HOBt was replaced with Cl-HOBt, and the nuclear magnetic calculation yield was 92%.
EXAMPLE 28 Synthesis of Compound of formula 1 (N-tert-butyl-3- ((5-methyl-2- ((4- (2-pyrrolidin-1-ylethoxy) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide)
Except for replacing 1,1,3, 3-tetramethyldisiloxane by methyldiethoxysilane, the reaction was carried out in the same manner as in example 25, and the nuclear magnetic computation yield was 96%.
EXAMPLE 29 Synthesis of the Compound of formula 1 (N- ((3s,5s,7s) -adamantan-1-yl) -3- ((5-methyl-2- ((4- (2- (pyrrolidinyl-1-yl) ethoxy) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide)
A reaction flask was charged with the compound of formula 6 (3- (2- (4- (2- (pyrrolidinyl-1-yl) ethoxy) phenylamino) -5-methylpyrimidin-4-ylamino) benzenesulfonyl fluoride) (0.12mmol, 1.2eq), 125. mu.L of DMSO, 1-amantadine (15.1mg, 1.0eq), 0.01eq of HOBt, 2.0eq of N, N-diisopropylethylamine, 2.0eq of 1,1,3, 3-tetramethyldisiloxane and reacted at 25 ℃ for 24 hours. The detection result is as follows: ms (esi): 601.1[ M-H]-。
EXAMPLE 30 Synthesis of a Compound of formula 1 (3- ((5-methyl-2- ((4- (2- (pyrrolidinyl-1-yl) ethoxy) phenyl) amino) pyrimidin-4-yl) amino) -N- (2-phenylpropan-2-yl) benzenesulfonamide)
A reaction flask was charged with the compound of formula 6 (3- (2- (4- (2- (pyrrolidinyl-1-yl) ethoxy) phenylamino) -5-methylpyrimidin-4-ylamino) benzenesulfonyl fluoride) (0.12mmol, 1.2eq), 125. mu.L of DMSO, α, α -dimethylbenzylamine (13.5mg, 1.0eq), 0.01eq of HOBt, 2.0eq of N, N-diisopropylethylamine, 2.0eq of 1,1,3, 3-tetramethyldisiloxane, and reacted at 25 ℃ for 24 hours. The detection result is as follows: ms (esi): 585.1[ M-H]-。
EXAMPLE 31 Synthesis of Compound of formula 1 ((S) -3- ((5-methyl-2- ((4- (2- (pyrrolidinyl-1-yl) ethoxy) phenyl) amino) pyrimidin-4-yl) amino) -N- (1-phenylethyl) benzenesulfonamide)
To a reaction flask was added the compound of formula 6 (3- (2- (4- (2- (pyrrolidinyl-1-yl) ethoxy) phenylamino) -5-methylpyrimidin-4-ylamino) benzeneSulfonyl fluoride) (0.12mmol, 1.2eq), 125. mu.L of DMSO, S-phenethylamine (13.0. mu.L, 1.0eq), 0.01eq HOBt, 2.0eq N, N-diisopropylethylamine, 2.0eq 1,1,3, 3-tetramethyldisiloxane, reacted at 25 ℃ for 24 hours. The detection result is as follows: ms (esi): 571.1[ M-H]-。
Claims (10)
1. A compound of formula (4) or a salt thereof:
wherein X is F, Cl, Br or I, Z is H, C1-C10Alkyl radical, C1-C10Alkoxy, F, Cl, Br, I, CN, NO2、CF3Or C2-C10Ester group, G1、G2、G3、G4、G5Is N or CR ', wherein R' is selected from H, C1-C10Alkyl radical, C1-C10Alkoxy, CN, CF3、C2-C10Ester group, NO2F, Cl, Br or I, and G1To G5At least one of which is not N; y is F, Cl, Br, I, C1-C10Alkyl radical, C1-C10Alkoxy, CN, NO2、CF3Amino or C2-C10An ester group, and n is 0, 1,2, 3 or 4.
2. The compound of formula (4) according to claim 1, X is F, Cl or Br, Z is H, C1-C6Alkyl radical, C1-C6Alkoxy, F, Cl, Br, I, CN, NO2、CF3Or C2-C6Ester group, G1、G2、G3、G4、G5Is N or CR ', wherein R' is selected from H, C1-C6Alkyl radical, C1-C6Alkoxy, CN, CF3、C2-C6Ester group, NO2F, Cl, Br or I, and G1To G5At least two of which are not N; y is F, Cl、Br、I、C1-C6Alkyl radical, C1-C6Alkoxy, CN, NO2、CF3Amino or C2-C6An ester group, and n is 0, 1,2, 3 or 4.
4. a process for the preparation of a compound of formula (4), which comprises reacting a compound of formula (2) with a compound of formula (3) via nucleophilic substitution or coupling to give a compound of formula (4):
wherein, X, Z, G1、G2、G3、G4、G5Y and n are as defined in claim 1;
preferably, the compound of formula (2) is reacted with the compound of formula (3) in the presence of an organic solvent; the organic solvent is preferably a polar solvent, more preferably any one selected from water, methanol, ethanol, isopropanol, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, or any combination thereof;
the amount of the solvent is 1-10mL relative to 1mmol of the compound of formula (2);
the compound of formula (3) is used in an amount of 1 to 10 equivalents with respect to 1 equivalent of the compound of formula (2).
5. A compound of formula (6) or a salt thereof:
wherein R is10And R11The same or different, each independently selected from hydrogen and C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, above C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, optionally unsubstituted or substituted with one or more substituents each independently selected from the group consisting of1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, amino, hydroxyl, mercapto, carboxyl, C1-C6Alkoxy radical, C3-C18Cycloalkoxy, C6-C20Halogenated aryl, C2-C6Alkoxycarbonyl, acyloxy, amido, ureido, C1-C6Alkylsulfonyl radical, C6-C20Arylsulfonyl radical, C1-C6Haloalkyl, F, Cl, Br, I, cyano, nitro, nitroso, thiocyano, isothiocyanato, C1-C6Sulfanyl, C1-C6Sulfoalkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl as a substituent alone or in free combinationProvided that when R is10Or R11Any one of which is ethyl, butyl, trifluoroethyl, When the other is not H; or R10And R11Together with the N atom to which they are attached, form a heterocyclic group which is monocyclic, bicyclic or tricyclic, or which is a fused, bridged or spirocyclic ring, which heterocyclic group contains only one N atom or optionally in addition to the above-mentioned N atoms 1 or 2 or 3 heteroatoms selected from N, S and O, which heterocyclic group is unsubstituted or optionally substituted by one or more substituents each independently selected from the group consisting of C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, amino, hydroxyl, mercapto, carboxyl, C1-C6Alkoxy radical, C3-C8Cycloalkoxy, C2-C6Alkoxycarbonyl, F, Cl, Br, I, cyano, nitro, nitroso, amido, thiocyano, isothiocyanato, ureido, sulfo, alone or in combination; z is H, C1-C6Alkyl radical, C1-C6Alkoxy, F, Cl, Br, I, CN, NO2、CF3Or C2-C6Ester group with the proviso that when R10And R11And when H is the same, Z is not CN; g1、G2、G3、G4、G5Is N or CR ', wherein R' is selected from H, C1-C6Alkyl radical, C1-C6Alkoxy, CN, CF3、C2-C6Ester group, NO2F, Cl, Br or I, and G1To G5At least one of which is not N; y is F, Cl, Br, I,C1-C6Alkyl radical, C1-C6Alkoxy, CN, NO2、CF3Amino or C2-C6An ester group, and n is 0, 1,2, 3 or 4.
6. A compound of formula (6) according to claim 5, wherein R10And R11Independently selected from hydrogen, C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, above C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, optionally unsubstituted or substituted with one or more substituents each independently selected from the group consisting of1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, amino, hydroxyl, mercapto, carboxyl, C1-C6Alkoxy radical, C3-C18Cycloalkoxy, C2-C6Alkoxycarbonyl, acyloxy, amido, ureido, C1-C6Alkylsulfonyl radical, C6-C20Arylsulfonyl, F, Cl, Br, I, cyano, nitro, nitroso, thiocyano, isothiocyanato, C1-C6Sulfanyl, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl is taken as a substituent independently or is formed by free combination; with the proviso that when R10Or R11Any one of them is C1-C4Alkyl radical, C1-C2Haloalkyl, C substituted by hydroxy1-C6Alkyl, or anthracenedione substituted with amino, 4-sulfonylfluoroaniline, the other is not H; or R10And R11Together with the N atom to which they are attached, form a heterocyclic group which is monocyclic, bicyclic or tricyclic, or which is a fused, bridged or spirocyclic ring, which heterocyclic group contains only one N atom or optionally in addition to the above-mentioned N atoms 1 or 2 or 3 heteroatoms selected from N, S and O, which heterocyclic group is unsubstituted or optionally substituted by one or more substituents each independently selected from the group consisting of C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, amino, hydroxyl, mercapto, carboxyl, C1-C6Alkoxy radical, C3-C8Cycloalkoxy, C2-C6Alkoxycarbonyl, F, Cl, Br, I, cyano, nitro, nitroso, amido, thiocyano, isothiocyanato, ureido, sulfo, alone or in combination; g1To G5At least two of which are not N.
8. a process for the preparation of a compound of formula (6), which comprises reacting a compound of formula (4) with a compound of formula (5) via nucleophilic substitution or coupling to give a compound of formula (6):
wherein X is F, Cl, Br or I, G1、G2、G3、G4、G5、Y、n、Z、R10And R11As defined in claim 5;
preferably, the compound of formula (4) is reacted with the compound of formula (5) in the presence of an organic solvent and an acid; the organic solvent is preferably a polar solvent, more preferably selected from methanol, ethanol, isopropanol, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide or N-methylpyrrolidone; the acid is preferably concentrated hydrochloric acid, concentrated phosphoric acid, concentrated sulfuric acid or concentrated nitric acid, and more preferably concentrated hydrochloric acid or concentrated phosphoric acid;
the amount of the solvent is 1 to 10mL relative to 1mmol of the compound of formula (4);
the acid is used in an amount of 1 to 10 equivalents with respect to 1 equivalent of the compound of formula (4);
the compound of formula (5) is used in an amount of 1 to 10 equivalents with respect to 1 equivalent of the compound of formula (4).
9. Use of a compound according to any one of claims 1 to 8 or a salt thereof for the preparation of a sulfonamide compound.
10. A process for the preparation of a compound of formula (1) which comprises subjecting a compound of formula (6) and a compound of formula (7) to a nucleophilic substitution reaction to give a compound of formula (1), which reaction is carried out in the presence of a catalyst and optionally an additive or optionally a base:
wherein R is1And R2The same or different, each independently selected from hydrogen and C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, above C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, optionally unsubstituted or substituted with one or more substituents each independently selected from the group consisting of1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, amino, hydroxyl, mercapto, carboxyl, C1-C6Alkoxy radical, C3-C18Cycloalkoxy, C6-C20Halogenated aryl, C2-C6Alkoxycarbonyl, acyloxy, amido, ureido, C1-C6Alkylsulfonyl radical, C6-C20Arylsulfonyl radical, C1-C6Haloalkyl, F, Cl, Br, I, cyano, nitro, nitroso, thiocyano, isothiocyanato, C1-C6Sulfanyl, C1-C6Sulfoalkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl is taken as a substituent independently or is formed by free combination; or R10And R11Together with the N atom to which they are attached, form a heterocyclic group which may be monocyclic, bicyclic or tricyclic, or may be a fused, bridged or spirocyclic ring, said hetero ringThe heterocyclic group contains only one N atom or 1,2 or 3 additional hetero atoms selected from N, S and O besides the N atom, and the heterocyclic group is unsubstituted or optionally substituted by one or more substituents independently selected from C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C6-C20Aryl radical, C5-C20Heteroaryl group, C3-C18Heterocyclic group, C2-C6Alkenyl radical, C2-C6Alkynyl, amino, hydroxyl, mercapto, carboxyl, C1-C6Alkoxy radical, C3-C8Cycloalkoxy, C2-C6Alkoxycarbonyl, F, Cl, Br, I, cyano, nitro, nitroso, amido, thiocyano, isothiocyanato, ureido, sulfo, alone or in combination; g1、G2、G3、G4、G5、Y、n、Z、R10And R11As defined in claim 5;
the catalyst is a compound shown as a formula (I) or a compound shown as a formula (II) or a combination thereof:
in the formulae (I) and (II), R1And R2Are each independently of the others selected from hydrogen, hydroxy, F, Cl, Br, I, C1-C6Alkyl radical, NO2、C1-C6Alkoxy, amino, C1-C6Alkyl monosubstituted amino, C1-C6Alkyl-disubstituted amino, C1-C6Haloalkyl, C1-C6An alkyloxycarbonyl group; or R1And R2Together with the carbon atom to which they are attached form ring a;
the ring A is selected from: a monocyclic or compensated bicyclic aromatic ring having 6-10 carbon atoms; a monocyclic or compensated bicyclic heteroaryl ring having 5-10 ring atoms comprising 1-3 heteroatoms selected from N, O, S and any combination thereof; a monocyclic or fused bicyclic carbocycle having 3-10 carbon atoms; a monocyclic or compensated bicyclic heterocycle having 3-10 ring atoms comprising 1-3 heteroatoms selected from N, O, S and any combination thereof;
said ring A being optionally substituted by one or more than one substituent RaSubstituted, each substituent RaIdentical or different, independently of one another, from the group consisting of hydroxyl, F, Cl, Br, I, C1-C18Alkyl radical, NO2、C1-C18Alkoxy, amino, C1-C6Alkyl monosubstituted amino, C1-C6Alkyl-disubstituted amino, C1-C6Haloalkyl, C1-C6Alkyl oxycarbonyl radical, C6-C10Aryl, benzyl;
R3are respectively selected from hydrogen, hydroxyl, sulfydryl, F, Cl, Br, I and C1-C6Alkyl radical, NO2、C1-C6Alkoxy, amino, C1-C6Alkyl monosubstituted amino, C1-C6Alkyl-disubstituted amino, C1-C6Haloalkyl, C1-C18Alkyloxycarbonyl, oxytris (pyrrolidinyl) phosphonium hexafluorophosphate, oxytris (pyrrolidinyl) phosphonium tetrafluoroborate, oxytris (dimethylamino) phosphonium hexafluorophosphate, oxytris (dimethylamino) phosphonium tetrafluoroborate, oxydi (dimethylamino) carbonium hexafluorophosphate, oxydi (dimethylamino) carbonium tetrafluoroborate, oxydi (pyrrolidinyl) carbonium hexafluorophosphate, oxydi (pyrrolidinyl) carbonium tetrafluoroborate, -OSO2C1-C6Alkyl, -OSO2C1-C8Perfluoroalkyl group, -OSO2C6-C10An aryl group;
preferably, the catalyst is selected from any one of the following compounds or any combination thereof:
the additive is a silicon-containing compound selected from the group consisting of:
unsubstituted or substituted trimethylsilyl, C1-C4Alkyl radical, C1-C4Haloalkyl, phenyl, C1-C4Alkoxy or any combination thereof mono-or poly-substituted silane;
unsubstituted or by C1-C4Alkyl radical, C1-C4Haloalkyl, phenyl, C1-C4Alkoxy or any combination thereof mono-or poly-substituted disiloxane;
a compound of formula (III)Wherein the substituent Re、Rf、Rg、Rh、Ri、Rj、RkIdentical or different, independently of one another, from hydrogen, C1-C4Alkyl radical, C1-C4Haloalkyl, phenyl, C1-C4An alkoxy group;
a compound of formula (IV)Wherein R isl、Rm、Rn、Ro、Rp、RqIdentical or different, independently of one another, from hydrogen, C1-C4Alkyl radical, C1-C4Haloalkyl, phenyl, C1-C4An alkoxy group;
a compound of formula (V)Wherein R isr、Rs、Rt、Ru、Rv、Rw、Rx、RySame or differentAnd independently of each other from hydrogen, C1-C4Alkyl radical, C1-C4Haloalkyl, phenyl, C1-C4Alkoxy, n is 1 to 2000, preferably 10 to 1000, more preferably 100-500;
preferably, the additive is selected from (TMS)2O, 1,1,3, 3-tetramethyldisiloxane, methyldiethoxysilane, silica gels, where n is 1-2000, preferably 10-1000, more preferably 100-500C3H9OSi·(CH4OSi)n·C3H9Si or any one or any combination of the following compounds:
more preferably, the additive is selected from (TMS)2O, 1,3, 3-tetramethyldisiloxane, methyldiethoxysilane, or any combination thereof;
the alkali is organic alkali or inorganic alkali, and the organic alkali is selected from: r11R12NR13Wherein R is11、R12And R13Independently of one another, from hydrogen, C1-C4An alkyl group; r21R22N-Y-NR23R24Y is C1-C3Alkylene radical, R21、R22、R23And R24Independently of one another, from hydrogen, C1-C4An alkyl group; unsubstituted or substituted by halogen, C1-C4Alkyl-substituted diaza or triazabicyclo C6-C12An olefin;
the inorganic base is selected from carbonates, phosphates, hydrides and C of alkali metals or alkaline earth metals1-C18An alkyl oxide;
preferably, the base is selected from triethylamine, diisopropyldiethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5, 7-triazabicyclo [4.4.0] dec-5-ene (TBD), 1, 4-diazabicyclo [2.2.2] octane (DABCO), potassium carbonate, cesium carbonate, potassium phosphate, 2-tert-butylimino-2-diethylamino-1, 3-dimethylperhydro-1, 3, 2-diazaphosphorus (BEMP) and 2-tert-butyl-1, 1,3, 3-tetramethylguanidine (Barton base);
more preferably, the base is triethylamine or diisopropylethylamine;
the catalyst is used in an amount of 0.0001 to 2.0 equivalents with respect to 1 equivalent of the compound of formula (6);
the additive is used in an amount of 0 to 10 equivalents with respect to 1 equivalent of the compound of formula (6);
the base is used in an amount of 0 to 10 equivalents with respect to 1 equivalent of the compound of formula (6);
the amount of the solvent is 1 to 10mL relative to 1mmol of the compound of formula (6);
the compound of formula (7) is used in an amount of 0.2 to 10 equivalents with respect to 1 equivalent of the compound of formula (6).
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010879059.8A CN112110863A (en) | 2020-08-27 | 2020-08-27 | Sulfonyl fluoride compound, preparation method thereof and method for preparing sulfonamide compound through sulfonyl fluoride compound |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010879059.8A CN112110863A (en) | 2020-08-27 | 2020-08-27 | Sulfonyl fluoride compound, preparation method thereof and method for preparing sulfonamide compound through sulfonyl fluoride compound |
Publications (1)
Publication Number | Publication Date |
---|---|
CN112110863A true CN112110863A (en) | 2020-12-22 |
Family
ID=73804953
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202010879059.8A Pending CN112110863A (en) | 2020-08-27 | 2020-08-27 | Sulfonyl fluoride compound, preparation method thereof and method for preparing sulfonamide compound through sulfonyl fluoride compound |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN112110863A (en) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1419548A (en) * | 2000-03-28 | 2003-05-21 | 阿斯特拉曾尼卡有限公司 | 4-amino-5-cyano-2-anilino-pyrimidine derivatives and their use as inhbitors of cell-cycle kinases |
CN1454210A (en) * | 2000-07-11 | 2003-11-05 | 阿斯特拉曾尼卡有限公司 | Pyrimidine derivatives |
CN1633419A (en) * | 2001-05-29 | 2005-06-29 | 舍林股份公司 | CDK-inhibitory pyrimidines, their production and use as pharmaceutical agents |
US20060252748A1 (en) * | 2005-02-17 | 2006-11-09 | Bernhard Lindenthal | Use of CDK II inhibitors for birth control |
CN101228118A (en) * | 2005-07-21 | 2008-07-23 | 惠氏公司 | Process for the synthesis of sulfonyl halides and sulfonamides from sulfonic acid salts |
-
2020
- 2020-08-27 CN CN202010879059.8A patent/CN112110863A/en active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1419548A (en) * | 2000-03-28 | 2003-05-21 | 阿斯特拉曾尼卡有限公司 | 4-amino-5-cyano-2-anilino-pyrimidine derivatives and their use as inhbitors of cell-cycle kinases |
CN1454210A (en) * | 2000-07-11 | 2003-11-05 | 阿斯特拉曾尼卡有限公司 | Pyrimidine derivatives |
CN1633419A (en) * | 2001-05-29 | 2005-06-29 | 舍林股份公司 | CDK-inhibitory pyrimidines, their production and use as pharmaceutical agents |
US20060252748A1 (en) * | 2005-02-17 | 2006-11-09 | Bernhard Lindenthal | Use of CDK II inhibitors for birth control |
CN101228118A (en) * | 2005-07-21 | 2008-07-23 | 惠氏公司 | Process for the synthesis of sulfonyl halides and sulfonamides from sulfonic acid salts |
Non-Patent Citations (2)
Title |
---|
H. C. FIELDING,ET AL: "Reactions of polyfluoroarenes with hexamethyldisilazane and with 1,1,1-trimethyl-N,N-bis(trimethylsilyl)stannanamine in the presence of caesium fluoride", 《JOURNAL OF FLUORINE CHEMISTRY》, vol. 75, no. 2, pages 169 - 172, XP004020479, DOI: 10.1016/0022-1139(95)03269-6 * |
卢圣栋: "现代分子生物学实验技术", 31 December 1999, 中国协和医科大学出版社, pages: 501 - 503 * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA3150515A1 (en) | Mta-cooperative prmt5 inhibitors | |
AU2024200464A1 (en) | Amine-substituted aryl or heteroaryl compounds as ehmt1 and ehmt2 inhibitors | |
ES2965081T3 (en) | 4-Aminopyrazolo[3,4-d]pyrimidinyl-azabicyclo derivatives and pharmaceutical composition comprising said derivatives | |
ES2404415T3 (en) | Imidazo [1,2-a] pyrazine compounds for the treatment of viral infections such as hepatitis | |
RU2727772C1 (en) | Pyrimidine derivatives against influenza virus | |
AU2018253655B2 (en) | Novel inhibitor of cyclin-dependent kinase CDK9 | |
CN110092787B (en) | Preparation and application of compound or medicinal salt or composition thereof | |
AU2014400628A1 (en) | Aminopyridazinone compounds as protein kinase inhibitors | |
AU2016254385A1 (en) | JAK inhibitors | |
AU2015276699B2 (en) | Pyridino[1,2-a]pyrimidone analogue used as PI3K inhibitor | |
CN102153519B (en) | Preparation method of quinazoline derivative | |
KR20200115583A (en) | 2H-indazole derivatives as CDK4 and CDK6 inhibitors and their therapeutic use | |
CN106432311A (en) | Processes and intermediates for producing azaindoles | |
CA2823969A1 (en) | 2,4-diamino-6,7-dihydro-5h-pyrrolo[2,3]pyrimidine derivatives as fak/pyk2 inhibitors | |
CN114685487B (en) | Pyrimidine heterocyclic compounds, preparation method and application | |
WO2021226547A2 (en) | Targeted nek7 inhibition for modulation of the nlrp3 inflammasome | |
MX2014009944A (en) | Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme. | |
CA3134779A1 (en) | Prmt5 inhibitors and uses thereof | |
US11325912B2 (en) | Regio-selective synthesis of imidazo[1,2-a]pyrimidines | |
CN114524810B (en) | Pyrimidine heterocyclic compounds, preparation method and application | |
EP2867221B1 (en) | Cyanoguanidines and their sue as antiviral agents. | |
CN112110863A (en) | Sulfonyl fluoride compound, preparation method thereof and method for preparing sulfonamide compound through sulfonyl fluoride compound | |
CN104804001B9 (en) | 4-substituted pyrrolo [2,3-d ] pyrimidine compounds and uses thereof | |
CA3043948C (en) | Fgfr4 inhibitor and preparation method and use thereof | |
CN114907350B (en) | Nitrogen-containing condensed ring compound, preparation method and application |
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 |