KR20230087741A - Spiro[indoline-3,2'-piperidin] derivatives and method for producing the same - Google Patents
Spiro[indoline-3,2'-piperidin] derivatives and method for producing the same Download PDFInfo
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- KR20230087741A KR20230087741A KR1020210176246A KR20210176246A KR20230087741A KR 20230087741 A KR20230087741 A KR 20230087741A KR 1020210176246 A KR1020210176246 A KR 1020210176246A KR 20210176246 A KR20210176246 A KR 20210176246A KR 20230087741 A KR20230087741 A KR 20230087741A
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- Prior art keywords
- spiro
- indoline
- piperidine
- formula
- compound
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- MOZQRNBSHJQWHC-UHFFFAOYSA-N spiro[1,2-dihydroindole-3,2'-piperidine] Chemical class C1NC2=CC=CC=C2C11CCCCN1 MOZQRNBSHJQWHC-UHFFFAOYSA-N 0.000 title claims abstract description 40
- 238000004519 manufacturing process Methods 0.000 title claims description 5
- -1 allyl compound Chemical class 0.000 claims abstract description 37
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 28
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 11
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 102
- 230000015572 biosynthetic process Effects 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 17
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 10
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical group C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 125000003003 spiro group Chemical group 0.000 claims description 8
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- STMPXDBGVJZCEX-UHFFFAOYSA-N triethylsilyl trifluoromethanesulfonate Chemical compound CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F STMPXDBGVJZCEX-UHFFFAOYSA-N 0.000 claims description 6
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 claims description 6
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical group C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 229910021617 Indium monochloride Inorganic materials 0.000 claims description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 4
- CTIKAHQFRQTTAY-UHFFFAOYSA-N fluoro(trimethyl)silane Chemical compound C[Si](C)(C)F CTIKAHQFRQTTAY-UHFFFAOYSA-N 0.000 claims description 4
- APHGZSBLRQFRCA-UHFFFAOYSA-M indium(1+);chloride Chemical compound [In]Cl APHGZSBLRQFRCA-UHFFFAOYSA-M 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 abstract description 14
- 239000012038 nucleophile Substances 0.000 abstract description 11
- 150000003413 spiro compounds Chemical class 0.000 abstract description 8
- 238000005937 allylation reaction Methods 0.000 abstract description 7
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 abstract description 5
- 238000007040 multi-step synthesis reaction Methods 0.000 abstract description 4
- 230000008569 process Effects 0.000 abstract description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 69
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 46
- 238000005481 NMR spectroscopy Methods 0.000 description 38
- 239000000126 substance Substances 0.000 description 27
- 235000019439 ethyl acetate Nutrition 0.000 description 23
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- PCKPVGOLPKLUHR-UHFFFAOYSA-N OH-Indolxyl Natural products C1=CC=C2C(O)=CNC2=C1 PCKPVGOLPKLUHR-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 229910052723 transition metal Inorganic materials 0.000 description 4
- 150000003624 transition metals Chemical class 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- KYFXPHPBTUJULU-UHFFFAOYSA-N 2-(2-methoxyanilino)-2-(2-phenylmethoxyphenyl)acetonitrile Chemical compound COC1=CC=CC=C1NC(C#N)C1=CC=CC=C1OCC1=CC=CC=C1 KYFXPHPBTUJULU-UHFFFAOYSA-N 0.000 description 2
- UOXJNGFFPMOZDM-UHFFFAOYSA-N 2-[di(propan-2-yl)amino]ethylsulfanyl-methylphosphinic acid Chemical compound CC(C)N(C(C)C)CCSP(C)(O)=O UOXJNGFFPMOZDM-UHFFFAOYSA-N 0.000 description 2
- FJXJAAFKONAPKR-UHFFFAOYSA-N 4-methoxy-2-nitrobenzo[e][1]benzofuran Chemical compound COC1=CC2=CC=CC=C2C2=C1OC([N+]([O-])=O)=C2 FJXJAAFKONAPKR-UHFFFAOYSA-N 0.000 description 2
- NYIVWTWKIQOBKO-UHFFFAOYSA-N 4-phenanthren-3-ylbutanoic acid Chemical compound C1=CC=C2C3=CC(CCCC(=O)O)=CC=C3C=CC2=C1 NYIVWTWKIQOBKO-UHFFFAOYSA-N 0.000 description 2
- QDDQSSZZYNCVHC-UHFFFAOYSA-N 5-[(4-tert-butylphenoxy)carbonylamino]-2-hydroxybenzoic acid Chemical compound C1=CC(C(C)(C)C)=CC=C1OC(=O)NC1=CC=C(O)C(C(O)=O)=C1 QDDQSSZZYNCVHC-UHFFFAOYSA-N 0.000 description 2
- YBGOLOJQJWLUQP-UHFFFAOYSA-O 7-(dimethylamino)-4-hydroxy-3-oxophenoxazin-10-ium-1-carboxylic acid Chemical compound OC(=O)C1=CC(=O)C(O)=C2OC3=CC(N(C)C)=CC=C3[NH+]=C21 YBGOLOJQJWLUQP-UHFFFAOYSA-O 0.000 description 2
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 2
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940000406 drug candidate Drugs 0.000 description 2
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N fluorene Chemical compound C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- UGUHFDPGDQDVGX-UHFFFAOYSA-N 1,2,3-thiadiazole Chemical group C1=CSN=N1 UGUHFDPGDQDVGX-UHFFFAOYSA-N 0.000 description 1
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical group C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 1
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 1
- 125000000355 1,3-benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical group C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- HTFNVAVTYILUCF-UHFFFAOYSA-N 2-[2-ethoxy-4-[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]anilino]-5-methyl-11-methylsulfonylpyrimido[4,5-b][1,4]benzodiazepin-6-one Chemical compound CCOc1cc(ccc1Nc1ncc2N(C)C(=O)c3ccccc3N(c2n1)S(C)(=O)=O)C(=O)N1CCC(CC1)N1CCN(C)CC1 HTFNVAVTYILUCF-UHFFFAOYSA-N 0.000 description 1
- SFHYNDMGZXWXBU-LIMNOBDPSA-N 6-amino-2-[[(e)-(3-formylphenyl)methylideneamino]carbamoylamino]-1,3-dioxobenzo[de]isoquinoline-5,8-disulfonic acid Chemical compound O=C1C(C2=3)=CC(S(O)(=O)=O)=CC=3C(N)=C(S(O)(=O)=O)C=C2C(=O)N1NC(=O)N\N=C\C1=CC=CC(C=O)=C1 SFHYNDMGZXWXBU-LIMNOBDPSA-N 0.000 description 1
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 1
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 1
- 102000004136 Vasopressin Receptors Human genes 0.000 description 1
- 108090000643 Vasopressin Receptors Proteins 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical group C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000002676 chrysenyl group Chemical group C1(=CC=CC=2C3=CC=C4C=CC=CC4=C3C=CC12)* 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- TXCDCPKCNAJMEE-UHFFFAOYSA-N dibenzofuran Chemical group C1=CC=C2C3=CC=CC=C3OC2=C1 TXCDCPKCNAJMEE-UHFFFAOYSA-N 0.000 description 1
- 125000005509 dibenzothiophenyl group Chemical group 0.000 description 1
- 125000000532 dioxanyl group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000003914 fluoranthenyl group Chemical group C1(=CC=C2C=CC=C3C4=CC=CC=C4C1=C23)* 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 229960003299 ketamine Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000000737 periodic effect Effects 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
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
- 125000004625 phenanthrolinyl group Chemical group N1=C(C=CC2=CC=C3C=CC=NC3=C12)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000001725 pyrenyl group Chemical group 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical group C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 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
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000001544 thienyl 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
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
Abstract
본 발명은 스피로[인돌린-3,2'-피페리딘] 유도체 및 이의 제조 방법에 대한 것으로, 아이사틴 키티민과 알릴 화합물이 염기 하에서 극성 반전 알릴화 반응하고 합성 시약의 친핵체를 조절하여 아자-프린스 고리화 반응을 통해 스피로[인돌린-3,2'-피페리딘] 유도체를 합성한다. 특히, 다단계 합성 과정으로 C4' 위치에 치환되는 친핵체를 조절할 수 있는 6각 고리인 피페리딘 함유 스피로 화합물을 효과적으로 합성할 수 있다.The present invention relates to a spiro [indoline-3,2'-piperidine] derivative and a method for preparing the same, wherein isatine chitimine and an allyl compound undergo a polar inversion allylation reaction under a base, and the nucleophile of the synthetic reagent is controlled to form aza -Synthesis of spiro[indoline-3,2'-piperidine] derivatives through Prince cyclization. In particular, it is possible to effectively synthesize a six-membered ring piperidine-containing spiro compound that can control the nucleophile substituted at the C4' position through a multi-step synthesis process.
Description
본 발명은 스피로[인돌린-3,2'-피페리딘] 유도체 및 이의 제조 방법에 관한 것이다. 구체적으로, 아이사틴 키티민과 알릴 화합물이 염기 하에서 극성 반전 알릴화 반응하고 합성 시약의 친핵체를 조절하여 아자-프린스 고리화 반응을 통해 스피로[인돌린-3,2'-피페리딘] 유도체를 합성한다. 특히, 다단계 합성 과정으로 C4' 위치에 치환되는 친핵체를 조절할 수 있는 6각 고리인 피페리딘 함유 스피로 화합물을 효과적으로 합성할 수 있다.The present invention relates to spiro[indoline-3,2'-piperidine] derivatives and methods for their preparation. Specifically, aspiro[indoline-3,2'-piperidine] derivatives are produced through aza-prince cyclization reaction by a polar inversion allylation reaction between aisatin chitimine and an allyl compound in the presence of a base and controlling the nucleophile of the synthesis reagent. synthesize In particular, it is possible to effectively synthesize a six-membered ring piperidine-containing spiro compound that can control the nucleophile substituted at the C4' position through a multi-step synthesis process.
스피로 옥신돌은 천연물에서 많이 발견되는 물질로서 그들의 다양한 생화학적 활성으로 인해서 많은 관심을 받고 있다. 특정 스피로 옥신돌 유도체는 미국특허 제5,728,723호(Elf Sanofi)로부터 바소프레신 수용체 리간드의 합성에서 중간체로서 공지되어 있고, 국제특허출원 WO9741125(SKB), WO9711697(MSD), WO9527712(CEMAF) 및 WO9315051(Elf) 또한 합성 중간체로서 스피로 옥신돌을 개시하고 있다. Spiro oxindol is a substance found in many natural products and has received a lot of attention due to its various biochemical activities. Certain spirooxindole derivatives are known as intermediates in the synthesis of vasopressin receptor ligands from U.S. Pat. No. 5,728,723 (Elf Sanofi) and international patent applications WO9741125 (SKB), WO9711697 (MSD), WO9527712 (CEMAF) and WO9315051 (Elf). Also disclosed is spiro oxindole as a synthetic intermediate.
한편, CF3 작용기는 생화학적 활성분자에 존재할 경우, 대사 안정성, 생체 이용률, 친유성 등을 향상시키는 것으로 알려져 있다. On the other hand, CF 3 functional group is known to improve metabolic stability, bioavailability, lipophilicity, etc. when present in biochemically active molecules.
따라서 CF3 작용기를 포함하는 스피로옥신돌을 합성하고자 노력하고 있으나, 6각 고리인 피페리딘 함유 스피로 화합물의 합성을 위한 합성 방법은 전무한 상태이다.Therefore, efforts have been made to synthesize spirooxindole containing a CF 3 functional group, but there is no synthetic method for synthesizing a spiro compound containing 6-membered ring piperidine.
본원은 전술한 종래 기술의 문제점을 해결하기 위한 스피로[인돌린-3,2'-피페리딘] 유도체에 대한 것으로, 종래에 합성되지 않던 신규한 스피로[인돌린-3,2'-피페리딘] 유도체를 합성하여 의약 화학, 농화학, 재료화학 등 다양한 분야에서 응용될 수 있는 것을 첫 번째 목적으로 한다.The present invention relates to a spiro[indoline-3,2'-piperidine] derivative to solve the above-mentioned problems of the prior art, and is a novel spiro[indoline-3,2'-piperidine] that has not been synthesized in the past. Dean] The first purpose is to synthesize derivatives that can be applied in various fields such as medicinal chemistry, agricultural chemistry, and material chemistry.
또한, 본 발명의 스피로[인돌린-3,2'-피페리딘] 유도체의 제조 방법은 아이사틴 키티민과 알릴 화합물이 염기 하에서 극성 반전 알릴화 반응하고 합성 시약의 친핵체를 조절하여 아자-프린스 고리화 반응을 통해 스피로[인돌린-3,2'-피페리딘] 유도체를 합성할 수 있는 것을 두 번째 목적으로 한다. In addition, the method for preparing the spiro[indoline-3,2'-piperidine] derivative of the present invention is a polarity inversion allylation reaction between isatin chitimine and an allyl compound under a base, and the nucleophile of the synthetic reagent is adjusted to form an aza-prince The second object is to be able to synthesize a spiro[indoline-3,2'-piperidine] derivative through a cyclization reaction.
상기한 기술적 과제를 달성하기 위한 본 발명의 스피로[인돌린-3,2'-피페리딘] 유도체는 하기 화학식 1 로서 표시되는 화합물을 제공한다. The spiro [indoline-3,2'-piperidine] derivative of the present invention for achieving the above technical problem provides a compound represented by Formula 1 below.
[화학식 1][Formula 1]
상기 화학식 1에서, R1은 H 또는 C1-6의 알킬이고, R2 내지 R4는 각각 독립적으로 H, 할로겐, C1-6의 알킬, C1-6의 알콕시, -COOR5, 또는 -CN이고, R5는 H 또는 C1-6의 알킬이고, X는 F, Cl, Br, I, OH 또는 페닐싸이올(phenylthiol)인 것 일 수 있으나, 이에 제한되는 것은 아니다. In
상기 R1은 H 또는 메틸인 것 일 수 있으나, 이에 제한되는 것은 아니다. The R 1 may be H or methyl, but is not limited thereto.
상기 R2 내지 R4는 각각 독립적으로 H, 할로겐, 메틸, 메톡시기, -COOCH3, -CN 및 이들의 조합들로 이루어진 군에서 선택된 것을 포함하는 것 일 수 있으나, 이에 제한되는 것은 아니다. The R 2 to R 4 may each independently include one selected from the group consisting of H, halogen, methyl, methoxy group, -COOCH 3 , -CN, and combinations thereof, but is not limited thereto.
상기 스피로[인돌린-3,2'-피페리딘] 유도체는 하기 화합물 중 어느 하나를 선택하는 것 일 수 있으나, 이에 제한되는 것은 아니다: The spiro[indoline-3,2'-piperidine] derivative may be selected from any one of the following compounds, but is not limited thereto:
본 발명의 스피로[인돌린-3,2'-피페리딘] 유도체의 제조 방법은 하기 화학식 2로서 표시되는 화합물, 하기 화학식 3으로서 표시되는 화합물 및 염기를 용매 하에서 반응시켜 하기 화학식 4 로서 표시되는 화합물 및 하기 화학식 5로서 표시되는 화합물을 제조하는 단계; 및 상기 화학식 4 및 5로서 표시되는 화합물 및 합성 시약을 용매 하에서 반응시키는 단계;를 포함하며, 상기 합성 시약은 X를 포함하고, 하기 화학식 1 로서 표시되는 화합물을 합성하는 것을 제공한다: A method for producing a spiro[indoline-3,2'-piperidine] derivative of the present invention is to react a compound represented by Chemical Formula 2, a compound represented by Chemical Formula 3, and a base in a solvent to obtain a compound represented by Chemical Formula 4 Preparing a compound and a compound represented by Formula 5 below; and reacting the compound represented by Chemical Formulas 4 and 5 and a synthesis reagent in a solvent, wherein the synthesis reagent includes X, and a compound represented by Chemical Formula 1 is synthesized:
[화학식 1][Formula 1]
[화학식 2][Formula 2]
[화학식 3][Formula 3]
[화학식 4][Formula 4]
[화학식 5][Formula 5]
상기 화학식 1 내지 5에서, R1은 H 또는 C1-6의 알킬이고, R2 내지 R4는 각각 독립적으로 H, 할로겐, C1-6의 알킬, C1-6의 알콕시, -COOR5, 또는 -CN이고, R5는 H 또는 C1-6의 알킬이고, X는 F, Cl, Br, I, OH 또는 페닐싸이올(phenylthiol)이다.In
상기 반응은 화학식 2로서 표시되는 화합물과 상기 화학식 3으로서 표시되는 화합물이 상기 염기와 극성 반전 알릴화 반응으로 상기 화학식 4 로서 표시되는 화합물 및 상기 화학식 5로서 표시되는 화합물을 형성하는 것 일 수 있으나, 이에 제한되는 것은 아니다. In the reaction, the compound represented by Chemical Formula 2 and the compound represented by Chemical Formula 3 may form the compound represented by Chemical Formula 4 and the compound represented by Chemical Formula 5 through a polarity inversion allylation reaction with the base, It is not limited thereto.
상기 반응은 상기 화학식 4 로서 표시되는 화합물 및 상기 화학식 5로서 표시되는 화합물과 상기 합성 시약이 아자-프린스 고리화 반응을 수행하는 것 일 수 있으나, 이에 제한되는 것은 아니다. The reaction may be performed by performing an aza-prince cyclization reaction between the compound represented by Chemical Formula 4 and the compound represented by Chemical Formula 5 and the synthetic reagent, but is not limited thereto.
상기 합성 시약은 트리메틸실릴브로마이드(Trimethylsilyl bromide, TMSBr), 트리메틸실릴클로라이드(Trimethylsilyl chloride, TMSCl), 트리메틸실릴플루오라이드(Trimethylsilyl fluoride, TMSF), 트리메틸실릴아이오디드(Trimethylsilyl iodide, TMSI), 트리메틸실릴트리플레이트(Trimethylsilyl triflate, TMSOTf), 트리에틸실릴트리플레이트(Triethylsilyl triflate, TESOTf), BF3·OEt2, TiCl4, FeCl3, Cu(OTf)2, InCl3 및 이들의 조합들로 이루어진 군에서 선택된 것을 포함하는 것 일 수 있으나, 이에 제한되는 것은 아니다. The synthesis reagent is trimethylsilyl bromide (TMSBr), trimethylsilyl chloride (TMSCl), trimethylsilyl fluoride (TMSF), trimethylsilyl iodide (TMSI), trimethylsilyl triflate (Trimethylsilyl triflate, TMSOTf), triethylsilyl triflate (TESOTf), BF 3 · OEt 2 , TiCl 4 , FeCl 3 , Cu(OTf) 2 , InCl 3 and combinations thereof It may include, but is not limited thereto.
개시된 기술은 다음의 효과를 가질 수 있다. 다만, 특정 실시예가 다음의 효과를 전부 포함하여야 한다거나 다음의 효과만을 포함하여야 한다는 의미는 아니므로, 개시된 기술의 권리범위는 이에 의하여 제한되는 것으로 이해되어서는 아니 될 것이다.The disclosed technology may have the following effects. However, it does not mean that a specific embodiment must include all of the following effects or only the following effects, so it should not be understood that the scope of rights of the disclosed technology is limited thereby.
전술한 본원의 과제 해결 수단에 의하면, 본원에 따른 스피로[인돌린-3,2'-피페리딘] 유도체는 종래에 합성하기 어려웠던 신규한 스피로[인돌린-3,2'-피페리딘] 유도체를 합성하여 의약, 화학, 농화학, 재료화학 등 다양한 분야에서 응용할 수 있다. 특히, 6각 고리인 피페리딘(piperidin)과 옥신돌(oxindole)이 스피로 화합물을 합성하기 위한 방법은 종래에는 전무하였다.According to the above-described means for solving the problems of the present application, the spiro[indoline-3,2'-piperidine] derivative according to the present application is a novel spiro[indoline-3,2'-piperidine] that has been difficult to synthesize in the past. Derivatives can be synthesized and applied in various fields such as medicine, chemistry, agricultural chemistry, and material chemistry. In particular, there has been no conventional method for synthesizing a spiro compound using six-membered rings, piperidin and oxindole.
본원의 스피로[인돌린-3,2'-피페리딘] 유도체의 제조 방법은 종래에 전무하던 피페리딘과 옥신돌의 스피로 화합물을 합성할 수 있다. 특히, 전이금속의 부재 하에서 단일 단계로 온화한 조건에서 합성할 수 있다. 종래에 출원한 10-2021-0043490호에서는 단일반응으로 C4'에 위치한 친핵체의 치환기를 조절하는 데에 한계가 있었다. 하지만, 본원은 다단계 합성으로 합성 시약의 친핵체를 조절하여 C4'의 치환기를 용이하게 조절할 수 있다.The preparation method of the spiro [indoline-3,2'-piperidine] derivative of the present application can synthesize a spiro compound of piperidine and oxindole, which has not been previously available. In particular, it can be synthesized under mild conditions in a single step in the absence of a transition metal. In the prior application No. 10-2021-0043490, there was a limit to controlling the substituent of the nucleophile located at C4' in a single reaction. However, in the present invention, the substituent of C4' can be easily controlled by controlling the nucleophile of the synthesis reagent through multi-step synthesis.
또한, 치환기를 다양하게 조절함으로써 다양한 스피로[인돌린-3,2'-피페리딘] 유도체를 제조할 수 있다. In addition, various spiro[indoline-3,2'-piperidine] derivatives can be prepared by adjusting the substituents in various ways.
나아가, 스피로[인돌린-3,2'-피페리딘] 유도체는 다양한 생화학적 활성을 가지고 있어 다양한 의약품 후보 물질의 합성을 가능하게 하고, 이에 따라 다양한 신약 개발을 가능하게 할 수 있다.Furthermore, spiro[indoline-3,2'-piperidine] derivatives have various biochemical activities, enabling the synthesis of various drug candidates and, accordingly, the development of various new drugs.
도 1은 본원의 일 구현예에 따른 스피로[인돌린-3,2'-피페리딘] 유도체의 합성 메커니즘을 나타낸 도면이다.1 is a diagram showing a synthesis mechanism of a spiro[indoline-3,2'-piperidine] derivative according to one embodiment of the present application.
본 발명은 다양한 변경을 가할 수 있고 여러 가지 실시예를 가질 수 있는 바, 특정 실시예들을 도면에 예시하고 상세한 설명에 구체적으로 설명하고자 한다. 그러나 이는 본 발명을 특정한 실시 형태에 대해 한정하려는 것이 아니며, 본 발명의 사상 및 기술 범위에 포함되는 모든 변경, 균등물 내지 대체물을 포함하는 것으로 이해되어야 한다.Since the present invention can make various changes and have various embodiments, specific embodiments will be illustrated in the drawings and described in detail in the detailed description. However, this is not intended to limit the present invention to specific embodiments, and should be understood to include all modifications, equivalents, or substitutes included in the spirit and technical scope of the present invention.
각 도면을 설명하면서 유사한 참조부호를 유사한 구성요소에 대해 사용한다. 제 1, 제 2등의 용어는 다양한 구성요소들을 설명하는데 사용될 수 있지만, 상기 구성요소들은 상기 용어들에 의해 한정되어서는 안 된다. 상기 용어들은 하나의 구성요소를 다른 구성요소로부터 구별하는 목적으로만 사용된다.In describing each figure, like reference numbers are used for like elements. Terms such as first and second may be used to describe various components, but the components should not be limited by the terms. These terms are only used for the purpose of distinguishing one component from another.
예를 들어, 본 발명의 권리 범위를 벗어나지 않으면서 제 1 구성요소는 제 2 구성요소로 명명될 수 있고, 유사하게 제 2 구성요소도 제 1 구성요소로 명명될 수 있다. "및/또는" 이라는 용어는 복수의 관련된 기재된 항목들의 조합 또는 복수의 관련된 기재된 항목들 중의 어느 항목을 포함한다. For example, a first element may be termed a second element, and similarly, a second element may be termed a first element, without departing from the scope of the present invention. The term "and/or" includes any combination of a plurality of related listed items or any of a plurality of related listed items.
다르게 정의되지 않는 한, 기술적이거나 과학적인 용어를 포함해서 여기서 사용되는 모든 용어들은 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자에 의해 일반적으로 이해되는 것과 동일한 의미가 있다. Unless defined otherwise, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention belongs.
일반적으로 사용되는 사전에 정의되어 있는 것과 같은 용어들은 관련 기술의 문맥상 가지는 의미와 일치하는 의미가 있는 것으로 해석되어야 하며, 본 출원에서 명백하게 정의하지 않는 한, 이상적이거나 과도하게 형식적인 의미로 해석되지 않아야 한다. Terms such as those defined in commonly used dictionaries should be interpreted as having meanings consistent with the meanings in the context of the related art, and unless explicitly defined in this application, they should not be interpreted in ideal or excessively formal meanings. Should not be.
본원 명세서 전체에서, 어떤 부재가 다른 부재 "상에", "상부에", "상단에", "하에", "하부에", "하단에" 위치하고 있다고 할 때, 이는 어떤 부재가 다른 부재에 접해 있는 경우뿐 아니라 두 부재 사이에 또 다른 부재가 존재하는 경우도 포함한다.Throughout the present specification, when a member is referred to as being “on,” “above,” “on top of,” “below,” “below,” or “below” another member, this means that a member is located in relation to another member. This includes not only the case of contact but also the case of another member between the two members.
본원 명세서 전체에서, 어떤 부분이 어떤 구성요소를 "포함" 한다고 할 때, 이는 특별히 반대되는 기재가 없는 한 다른 구성요소를 제외하는 것이 아니라 다른 구성 요소를 더 포함할 수 있는 것을 의미한다.Throughout the present specification, when a part "includes" a certain component, it means that it may further include other components without excluding other components unless otherwise stated.
본 명세서에서 사용되는 정도의 용어 "약", "실질적으로" 등은 언급된 의미에 고유한 제조 및 물질 허용오차가 제시될 때 그 수치에서 또는 그 수치에 근접한 의미로 사용되고, 본원의 이해를 돕기 위해 정확하거나 절대적인 수치가 언급된 개시 내용을 비양심적인 침해자가 부당하게 이용하는 것을 방지하기 위해 사용된다. 또한, 본원 명세서 전체에서, "~ 하는 단계" 또는 "~의 단계"는 "~를 위한 단계"를 의미하지 않는다. As used herein, the terms "about," "substantially," and the like are used at or approximating that number when manufacturing and material tolerances inherent in the stated meaning are given, and are intended to assist in the understanding of this disclosure. Accurate or absolute figures are used to prevent undue exploitation by unscrupulous infringers of the stated disclosure. In addition, throughout the present specification, “steps of” or “steps of” do not mean “steps for”.
본원 명세서 전체에서, 마쿠시 형식의 표현에 포함된 "이들의 조합"의 용어는 마쿠시 형식의 표현에 기재된 구성 요소들로 이루어진 군에서 선택되는 하나 이상의 혼합 또는 조합을 의미하는 것으로서, 상기 구성 요소들로 이루어진 군에서 선택되는 하나 이상을 포함하는 것을 의미한다.Throughout the present specification, the term "combination thereof" included in the expression of the Markush form means one or more mixtures or combinations selected from the group consisting of the components described in the expression of the Markush form, and the components It means including one or more selected from the group consisting of.
본원 명세서 전체에서, "A 및/또는 B" 의 기재는, "A 또는 B", 또는, "A 및 B" 를 의미한다.Throughout this specification, reference to "A and/or B" means "A or B" or "A and B".
본원 명세서 전체에서, 용어 "방향족 고리"는 C6-30의 방향족 탄화수소 고리기, 예를 들어, 페닐, 나프틸, 비페닐, 터페닐, 플루오렌, 페난트레닐, 트리페닐레닐, 페릴레닐, 크리세닐, 플루오란테닐, 벤조플루오레닐, 벤조트리페닐레닐, 벤조크리세닐, 안트라세닐, 스틸베닐, 파이레닐 등의 방향족 고리를 포함하는 것을 의미하며, "방향족 헤테로 고리"는 적어도 1 개의 헤테로 원소를 포함하는 방향족 고리로서, 예를 들어, 피롤릴, 피라지닐, 피리디닐, 인돌릴, 이소인돌릴, 푸릴, 벤조푸라닐, 이소벤조푸라닐, 디벤조푸라닐, 디벤조티오페닐, 퀴놀릴기, 이소퀴놀릴, 퀴녹살리닐, 카르바졸릴, 페난트리디닐, 아크리디닐, 페난트롤리닐, 티에닐, 및 피리딘 고리, 피라진 고리, 피리미딘 고리, 피리다진 고리, 트리아진 고리, 인돌 고리, 퀴놀린 고리, 아크리딘고리, 피롤리딘 고리, 디옥산 고리, 피페리딘 고리, 모르폴린 고리, 피페라진 고리, 카르바졸 고리, 푸란 고리, 티오펜 고리, 옥사졸 고리, 옥사디아졸 고리, 벤조옥사졸 고리, 티아졸 고리, 티아디아졸 고리, 벤조티아졸 고리, 트리아졸 고리, 이미다졸 고리, 벤조이미다졸 고리, 피란 고리, 디벤조푸란 고리로부터 형성되는 방향족 헤테로고리기를 포함하는 것을 의미한다.Throughout this specification, the term "aromatic ring" refers to a C 6-30 aromatic hydrocarbon ring group, for example, phenyl, naphthyl, biphenyl, terphenyl, fluorene, phenanthrenyl, triphenylenyl, perylenyl , Chrysenyl, fluoranthenyl, benzofluorenyl, benzotriphenylenyl, benzochrysenyl, anthracenyl, stilbenyl, means containing an aromatic ring such as pyrenyl, "aromatic heterocycle" is at least one As an aromatic ring containing a hetero element, for example, pyrrolyl, pyrazinyl, pyridinyl, indolyl, isoindolyl, furyl, benzofuranyl, isobenzofuranyl, dibenzofuranyl, dibenzothiophenyl, quinolyl group, isoquinolyl, quinoxalinyl, carbazolyl, phenanthridinyl, acridinyl, phenanthrolinyl, thienyl, and pyridine ring, pyrazine ring, pyrimidine ring, pyridazine ring, triazine ring, Indole ring, quinoline ring, acridine ring, pyrrolidine ring, dioxane ring, piperidine ring, morpholine ring, piperazine ring, carbazole ring, furan ring, thiophene ring, oxazole ring, oxadia Includes an aromatic heterocyclic group formed from a sol ring, a benzoxazole ring, a thiazole ring, a thiadiazole ring, a benzothiazole ring, a triazole ring, an imidazole ring, a benzoimidazole ring, a pyran ring, and a dibenzofuran ring means to do
본원 명세서 전체에서, 용어 "융합"은 2개 이상의 고리에 관하여, 적어도 한 쌍 이상의 인접 원자가 두 고리에 포함되는 것을 의미한다.Throughout this specification, the term "fused" with respect to two or more rings means that at least one pair of adjacent atoms are included in both rings.
본원 명세서 전체에서, 용어 “알킬”은 선형 또는 분지형의, 포화 또는 불포화의 C1-C6 알킬을 포함하는 것일 수 있으며, 예를 들어 메틸, 에틸, 프로필, 부틸, 펜틸, 헥실 또는 이들의 가능한 모든 이성질체를 포함하는 것일 수 있으나, 이에 제한되지 않을 수 있다.Throughout this specification, the term “alkyl” may include linear or branched, saturated or unsaturated C 1 -C 6 alkyl, for example methyl, ethyl, propyl, butyl, pentyl, hexyl or any of these It may include all possible isomers, but may not be limited thereto.
본원의 명세서 전체에서, 용어 "할로겐"은 주기율표의 17족 원소로서, 예를 들어, F, Cl, Br, 또는 I를 포함할 수 있으나, 이에 제한되지 않을 수 있다.Throughout the specification of the present application, the term "halogen" is a group 17 element of the periodic table, and may include, for example, F, Cl, Br, or I, but may not be limited thereto.
이하에서는 본원의 스피로[인돌린-3,2'-피페리딘] 유도체 및 이의 제조 방법에 대하여 구현예 및 실시예와 도면을 참조하여 구체적으로 설명하도록 한다. 그러나, 본원이 이러한 구현예 및 실시예와 도면에 제한되는 것은 아니다.Hereinafter, the spiro [indoline-3,2'-piperidine] derivative of the present application and its preparation method will be described in detail with reference to embodiments and examples and drawings. However, the present application is not limited to these embodiments and examples and drawings.
본원은, 하기 화학식 1로서 표시되는 스피로[인돌린-3,2'-피페리딘] 유도체에 관한 것이다.The present application relates to a spiro[indoline-3,2'-piperidine] derivative represented by
상기 화학식 1에서, R1은 H 또는 C1-6의 알킬이고, R2 내지 R4는 각각 독립적으로 H, 할로겐, C1-6의 알킬, C1-6의 알콕시, -COOR5, 또는 -CN이고, R5는 H 또는 C1-6의 알킬이고, X는 F, Cl, Br, I, OH 또는 페닐싸이올(phenylthiol)인 것 일 수 있으나, 이에 제한되는 것은 아니다.In
본원의 스피로[인돌린-3,2'-피페리딘] 유도체는 종래에 합성하기 어려웠던 신규한 스피로[인돌린-3,2'-피페리딘] 유도체를 합성하여 의약, 화학, 농화학, 재료화학 등 다양한 분야에서 응용할 수 있다. 특히, 6각 고리인 피페리딘(piperidin)과 옥신돌(oxindole)이 스피로 화합물을 합성하기 위한 방법은 종래에는 전무하였다. The spiro[indoline-3,2'-piperidine] derivative of the present application synthesizes a novel spiro[indoline-3,2'-piperidine] derivative that has been difficult to synthesize in the past and is used in medicine, chemistry, agricultural chemistry, and materials. It can be applied in various fields such as chemistry. In particular, there has been no conventional method for synthesizing a spiro compound using six-membered rings, piperidin and oxindole.
상기 R1은 H 또는 메틸인 것 일 수 있으나, 이에 제한되는 것은 아니다.The R 1 may be H or methyl, but is not limited thereto.
상기 R2 내지 R4는 각각 독립적으로 H, 할로겐, 메틸, 메톡시기, -COOCH3, -CN 및 이들의 조합들로 이루어진 군에서 선택된 것을 포함하는 것 일 수 있으나, 이에 제한되는 것은 아니다. The R 2 to R 4 may each independently include one selected from the group consisting of H, halogen, methyl, methoxy group, -COOCH 3 , -CN, and combinations thereof, but is not limited thereto.
상기 스피로[인돌린-3,2'-피페리딘] 유도체는 하기 화합물 중 어느 하나를 선택하는 것 일 수 있으나, 이에 제한되는 것은 아니다: The spiro[indoline-3,2'-piperidine] derivative may be selected from any one of the following compounds, but is not limited thereto:
본원은 하기 화학식 2로서 표시되는 화합물, 하기 화학식 3으로서 표시되는 화합물 및 염기를 용매 하에서 반응시켜 하기 화학식 4 로서 표시되는 화합물 및 하기 화학식 5로서 표시되는 화합물을 제조하는 단계; 및 상기 화학식 4 및 5로서 표시되는 화합물 및 합성 시약을 용매 하에서 반응시키는 단계;를 포함하며, 상기 합성 시약은 X를 포함하고, 상기 화학식 1 로서 표시되는 화합물을 합성하는 스피로[인돌린-3,2'-피페리딘] 유도체의 제조 방법에 관한 것이다. In the present application, a compound represented by
상기 화학식 2 내지 5에서, R1은 H 또는 C1-6의 알킬이고, R2 내지 R4는 각각 독립적으로 H, 할로겐, C1-6의 알킬, C1-6의 알콕시, -COOR5, 또는 -CN이고, R5는 H 또는 C1-6의 알킬이고, X는 F, Cl, Br, I, OH 또는 페닐싸이올(phenylthiol)이다.In
상기 화학식 2는 아이사틴(isatin)을 이용하여 합성한 키티민(ketamine)인 것 일 수 있다.
상기 반응은 화학식 2로서 표시되는 화합물과 상기 화학식 3으로서 표시되는 화합물이 상기 염기와 극성 반전 알릴화 반응으로 상기 화학식 4 로서 표시되는 화합물 및 상기 화학식 5로서 표시되는 화합물을 형성하는 것 일 수 있으나, 이에 제한되는 것은 아니다. In the reaction, the compound represented by
상기 반응은 상기 화학식 4 로서 표시되는 화합물 및 상기 화학식 5로서 표시되는 화합물과 상기 합성 시약이 아자-프린스 고리화 반응을 수행하는 것 일 수 있으나, 이에 제한되는 것은 아니다. The reaction may be performed by performing an aza-prince cyclization reaction between the compound represented by
도 1은 본원의 일 구현예에 따른 스피로[인돌린-3,2'-피페리딘] 유도체의 합성 메커니즘을 나타낸 도면이다. 1 is a diagram showing a synthesis mechanism of a spiro[indoline-3,2'-piperidine] derivative according to one embodiment of the present application.
도 1을 참조하면, 상기 화학식 2로서 표시되는 화합물과 상기 화학식 3으로서 표시되는 화합물이 상기 염기 하에서 극성 반전 알릴화 반응하여 상기 화학식 4로서 표시되는 화합물 및 상기 화학식 5로서 표시되는 화합물을 형성한다. 이어서, 상기 합성 시약과 아자-프린스 고리화 반응이 일어나 상기 화학식 4로서 표시되는 화합물 및 상기 화학식 5로서 표시되는 화합물은 각각 스피로[인돌린-3,2'-피페리딘] 유도체(1) 및 스피로[인돌린-3,2'-피페리딘] 유도체(1')로 합성된다. Referring to FIG. 1 , the compound represented by
상기 극성 반전 알릴화 반응의 온도 및 반응 시간과 상기 아자-프린스 고리화 반응의 온도 및 반응 시간은 같거나 서로 상이할 수 있다. The temperature and reaction time of the polarity inversion allylation reaction and the temperature and reaction time of the aza-prince cyclization reaction may be the same or different from each other.
본원의 스피로[인돌린-3,2'-피페리딘] 유도체의 제조 방법은 종래에 전무하던 피페리딘과 옥신돌의 스피로 화합물을 합성할 수 있다. 특히, 전이금속의 부재 하에서 단일 단계로 온화한 조건에서 합성할 수 있다. The preparation method of the spiro [indoline-3,2'-piperidine] derivative of the present application can synthesize a spiro compound of piperidine and oxindole, which has not been previously available. In particular, it can be synthesized under mild conditions in a single step in the absence of a transition metal.
종래에 출원한 10-2021-0043490호에서는 단일반응으로 C4'에 위치한 친핵체의 치환기를 조절하는 데에 한계가 있었다. 하지만, 본원은 다단계 합성으로 합성 시약의 친핵체를 조절하여 C4'의 치환기를 용이하게 조절할 수 있다. In the prior application No. 10-2021-0043490, there was a limit to controlling the substituent of the nucleophile located at C4' in a single reaction. However, in the present invention, the substituent of C4' can be easily controlled by controlling the nucleophile of the synthesis reagent through multi-step synthesis.
또한, 치환기를 다양하게 조절함으로써 다양한 스피로[인돌린-3,2'-피페리딘] 유도체를 제조할 수 있다. In addition, various spiro[indoline-3,2'-piperidine] derivatives can be prepared by adjusting the substituents in various ways.
나아가, 스피로[인돌린-3,2'-피페리딘] 유도체는 다양한 생화학적 활성을 가지고 있어 다양한 의약품 후보 물질의 합성을 가능하게 하고, 이에 따라 다양한 신약 개발을 가능하게 할 수 있다. Furthermore, spiro[indoline-3,2'-piperidine] derivatives have various biochemical activities, enabling the synthesis of various drug candidates and, accordingly, the development of various new drugs.
상기 합성 시약은 트리메틸실릴브로마이드(Trimethylsilyl bromide), 트리메틸실릴클로라이드(Trimethylsilyl chloride), 트리메틸실릴플루오라이드(Trimethylsilyl fluoride), 트리메틸실릴아이오디드(Trimethylsilyl iodide), 트리메틸실릴트리플레이트(Trimethylsilyl triflate), 트리에틸실릴트리플레이트(Triethylsilyl triflate), BF3·OEt2, TiCl4, FeCl3, Cu(OTf)2, InCl3 및 이들의 조합들로 이루어진 군에서 선택된 것을 포함하는 것 일 수 있으나, 이에 제한되는 것은 아니다.The synthesis reagent is trimethylsilyl bromide, trimethylsilyl chloride, trimethylsilyl fluoride, trimethylsilyl iodide, trimethylsilyl triflate, triethylsilyl Triflate (Triethylsilyl triflate), BF 3 · OEt 2 , TiCl 4 , FeCl 3 , Cu(OTf) 2 , InCl 3 and may include one selected from the group consisting of combinations thereof, but is not limited thereto. .
상기 합성 시약은 일반적으로 사용되는 아자-프린스 고리화 반응 시약인 것 일 수 있다. The synthetic reagent may be a generally used aza-prince cyclization reagent.
상기 염기는 1,8-디아자바이사이클로[5,4,0]언덱-7-엔 (1,8-Diazabicyclo[5.4.0]undec-7-ene, DBU), 트리에틸아민(triethylamine, TEA), 디이소프로필에틸아민(N,N-diisopropylethylamine, DIPEA), K2CO3, (CH3)3COK, Cs2CO3 및 이들의 조합들로 이루어진 군에서 선택된 것을 포함하는 것 일 수 있으나, 이에 제한되는 것은 아니다.The base is 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), triethylamine (TEA) , diisopropylethylamine (N,N-diisopropylethylamine, DIPEA), K 2 CO 3 , (CH 3 ) 3 COK, Cs 2 CO 3 , and may include one selected from the group consisting of combinations thereof, It is not limited thereto.
상기 용매는 디클로로에테인, 디클로로메테인, 아세토니트릴, 클로로포름, 테트라하이드로퓨란, 톨루엔 및 이들의 조합들로 이루어진 군에서 선택된 것을 포함하는 것 일 수 있으나, 이에 제한되는 것은 아니다.The solvent may include one selected from the group consisting of dichloroethane, dichloromethane, acetonitrile, chloroform, tetrahydrofuran, toluene, and combinations thereof, but is not limited thereto.
상기 반응은 -20℃ 내지 200℃의 온도 하에서 이루어지는 것 일 수 있으나, 이에 제한되는 것은 아니다.The reaction may be performed at a temperature of -20°C to 200°C, but is not limited thereto.
상기 반응이 -20℃ 미만 또는 200℃ 초과의 온도에서 이루어질 경우, 합성되는 스피로[인돌린-3,2'-피페리딘] 유도체의 수율이 감소될 수 있다. When the reaction is performed at a temperature of less than -20°C or more than 200°C, the yield of the synthesized spiro[indoline-3,2'-piperidine] derivative may decrease.
상기 반응은 200℃ 미만의 온화한 온도 조건에서 이루어진다. The reaction takes place under mild temperature conditions of less than 200 °C.
상기 반응은 1 분 내지 100 시간 동안 이루어지는 것 일 수 있으나, 이에 제한되는 것은 아니다.The reaction may be performed for 1 minute to 100 hours, but is not limited thereto.
상기 반응이 1 분 미만 동안 이루어지는 경우 반응물이 충분히 생성되지 않아 수율이 감소될 수 있다. 또한, 상기 반응이 100 시간 초과로 반응이 이루어지는 경우 부산물이 증가할 수 있다. 다만, 상기 반응 시간은 특별히 한정되지 않으며, 상기 반응 시간은 제조하고자 하는 화합물의 치환기에 따라 조절될 수 있다. 즉, 필요에 따라서는 상기에 개시한 반응 시간 범위 외의 반응 시간으로 이루어질 수 있다. If the reaction is performed for less than 1 minute, the yield may be reduced because the reactants are not sufficiently produced. In addition, when the reaction is performed for more than 100 hours, by-products may increase. However, the reaction time is not particularly limited, and the reaction time may be adjusted according to the substituent of the compound to be prepared. That is, if necessary, a reaction time outside the reaction time range disclosed above may be used.
이하 실시예를 통하여 본 발명을 더욱 상세하게 설명하고자 하나, 하기의 실시예는 단지 설명의 목적을 위한 것이며 본원의 범위를 한정하고자 하는 것은 아니다.The present invention will be described in more detail through the following examples, but the following examples are for illustrative purposes only and are not intended to limit the scope of the present application.
1.1. 반응 조건 최적화를 위한 실시예 및 합성 시약에 따른 합성 결과1.1. Synthesis Results According to Examples and Synthesis Reagents for Optimization of Reaction Conditions
먼저, 하기 반응식 1에서 1 당량(eq)(30 mg, 0.12 mmol)의 하기 화합물 A1, 3 당량(eq)(0.032 ml, 0.36 mmol)의 화합물 B1, 염기로서 1,8-디아자바이사이클로[5,4,0]언덱-7-엔 (1,8-Diazabicyclo[5.4.0]undec-7-ene, DBU) 1 당량(eq)(0.019 ml, 0.12 mmol) 및 용매로서 1.0 M 농도의 DCE(dichloroethane) 0.12 ml를 반응 용기에 넣고 -10℃의 온도에서 30분동안 혼합하여 하기 화합물 C1 및 C1'(1-methyl-3-((1,1,1-trifluoropent-4-en-2-yl)imino)indolin-2-one) 을 합성하였다. 이어서, 상기 화합물 C1 및 C1' 혼합물 30 mg을 1.0 M의 디클로로메테인 0.11 ml와 혼합한 후, 0.028 ml(0.22 mmol)의 BF3OEt2를 첨가하고 40℃의 온도에서 36시간동안 반응시켜 화합물 D1(4'-fluoro-1-methyl-6'-(trifluoromethyl)spiro[indoline-3,2'-piperidin]-2-one)을 제조하였다(0.037 mmol, 수율 34%). R f = 0.5 (EtOAc/Hexane = 1/4). Mp 166-167 °C; 1 H NMR (500 MHz, CDCl3): δ 7.37-7.33 (m, 2H), 7.11 (t, J = 7.2 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 5.58-5.42(m, 1H), 4.46-4.43 (m, 1H), 3.16 (s, 3H), 2.49-2.46 (m, 1H), 2.13-2.11 (m, 1H), 1.98-1.91 (m, 2H), 1.82-1.73 (m, 1H). 13 C NMR (125 MHz, CDCl3): δ 178.2, 142.9, 130.2, 130.0, 125.3 (C-F, q, 1 J CF = 277.4 Hz), 124.1, 123.5, 108.5, 85.2 (C-F, d, 1 J CF = 172.0 Hz), 60.9 (C-F, d, 3 J CF = 12.6 Hz), 51.3 (C-F, qd, 2 J CF = 29.8 Hz, 13.4 Hz), 38.1 (C-F, d, 2 J CF = 19.5 Hz), 30.9 (C-F, d, 2 J CF = 21.4 Hz), 26.0. IR: v 3310, 2921, 2849, 1706, 1614, 1473, 1376, 1278, 1155, 1131 cm1; HRMS (EI) m/z: [M]+ Calcd. for C14H14F4N2O 302.1042; Found 302.1042.First, in the following
[반응식 1][Scheme 1]
합성 시약으로서 트리에틸실릴트리플레이트를 24시간동안 반응시키는 것을 제외하고, 상기 실시예 1과 동일한 방법으로 화합물 D2(4'-Hydroxy-1-methyl-6'-(trifluoromethyl)spiro[indoline-3,2'-piperidin]-2-one)를 제조하였다(수율 40%). R f = 0.5 (EtOAc/Hexane = 1/2). Mp 207-208 °C; 1 H NMR (500 MHz, CDCl3): δ 7.35-7.32 (m, 2H), 7.13 (t, J = 7.7 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 5.58 (d, J = 11.5 Hz, 1H), 4.51-4.48 (m, 1H), 4.28 (s, 1H), 3.21 (s, 3H), 2.18-2.15 (m, 1H), 2.10-2.06 (m, 1H), 1.93-1.84 (m, 2H). 13 C NMR (150 MHz, CDCl3): δ 181.0, 142.3, 131.4, 129.9, 126.0 (C-F, q, 1 J CF = 231.0 Hz), 124.1, 124.0, 108.7, 64.3, 60.6, 48.2 (C-F, q, 2 J CF = 24.4 Hz), 36.3, 31.7, 26.3. IR: v 3400, 2938, 1682, 1613, 1472, 1169, 1132, 1091, 997 cm1; HRMS (FAB) m/z: [M+H]+ Calcd. for C14H16F3N2O2 301.1164; Found 301.1160.Compound D2 (4'-Hydroxy-1-methyl-6'-(trifluoromethyl)spiro[indoline-3, 2'-piperidin] -2-one) was prepared (yield: 40%). R f = 0.5 (EtOAc/Hexane = 1/2). Mp 207-208 °C; 1 H NMR (500 MHz, CDCl 3 ): δ 7.35-7.32 (m, 2H), 7.13 (t, J = 7.7 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 5.58 (d, J = 11.5 Hz, 1H), 4.51-4.48 (m, 1H), 4.28 (s, 1H), 3.21 (s, 3H), 2.18-2.15 (m, 1H), 2.10-2.06 (m, 1H), 1.93- 1.84 (m, 2H). 13 C NMR (150 MHz, CDCl 3 ): δ 181.0, 142.3, 131.4, 129.9, 126.0 (CF, q, 1 J CF = 231.0 Hz), 124.1, 124.0, 108.7, 64.3, 60.6, 48.2 (CF, q, 2 J CF = 24.4 Hz), 36.3, 31.7, 26.3. IR : v 3400, 2938, 1682, 1613, 1472, 1169, 1132, 1091, 997 cm 1 ; HRMS (FAB) m/z: [M+H] + Calcd. for C 14 H 16 F 3 N 2 O 2 301.1164; Found 301.1160.
[화합물 D2][Compound D2]
합성 시약으로서 트리메틸실릴트리플레이트를 사용하는 것을 제외하고, 상기 실시예 2와 동일한 방법으로 화합물 D2를 제조하였다(수율 30%). Compound D2 was prepared in the same manner as in Example 2, except that trimethylsilyl triflate was used as a synthesis reagent (yield: 30%).
합성 시약으로서 트리메틸실릴클로라이드를 7시간동안 반응시키는 것을 제외하고, 상기 실시예 1과 동일한 방법으로 화합물 D3(4'-Chloro-1-methyl-6'-(trifluoromethyl)spiro[indoline-3,2'-piperidin]-2-one)를 제조하였다(수율 90%). 1 H NMR (500 MHz, CDCl3): δ 7.36-7.32 (m, 2H), 7.11 (t, J = 7.7 Hz, 1H), 6.82 (d, J = 7.5 Hz, 1H), 4.90-4.84 (m, 1H), 4.51-4.48 (m, 1H), 3.16 (s, 3H), 2.53-2.50 (m, 1H), 2.19-2.08 (m, 2H), 1.92 (q, J = 12.0 Hz, 1H). 13 C NMR (150 MHz, CDCl3): δ 177.9, 142.6, 130.0, 129.7, 124.9 (C-F, q, 1 J CF = 231.3 Hz), 123.8, 123.3, 108.3, 60.7, 52.0 (C-F, q, 2 J CF = 24.7 Hz), 50.4, 42.1, 34.3, 25.8. IR: v 3447, 2922, 2852, 1701, 1613, 1471, 1277, 1149, 1131, 683 cm1; HRMS (EI) m/z: [M]+ Calcd for C14H14ClF3N2O 318.0747; Found 318.0747.Compound D3 (4'-Chloro-1-methyl-6'-(trifluoromethyl)spiro[indoline-3,2' -piperidin]-2-one) was prepared (yield: 90%). 1 H NMR (500 MHz, CDCl 3 ): δ 7.36-7.32 (m, 2H), 7.11 (t, J = 7.7 Hz, 1H), 6.82 (d, J = 7.5 Hz, 1H), 4.90-4.84 (m , 1H), 4.51–4.48 (m, 1H), 3.16 (s, 3H), 2.53–2.50 (m, 1H), 2.19–2.08 (m, 2H), 1.92 (q, J = 12.0 Hz, 1H). 13 C NMR (150 MHz, CDCl 3 ): δ 177.9, 142.6, 130.0, 129.7, 124.9 (CF, q, 1 J CF = 231.3 Hz), 123.8, 123.3, 108.3, 60.7, 52.0 (CF, q, 2 J CF = 24.7 Hz), 50.4, 42.1, 34.3, 25.8. IR : v 3447, 2922, 2852, 1701, 1613, 1471, 1277, 1149, 1131, 683 cm 1 ; HRMS (EI) m/z: [M] + Calcd for C 14 H 14 ClF 3 N 2 O 318.0747; Found 318.0747.
[화합물 D3][Compound D3]
용매로서 디클로로메테인을 사용하는 것을 제외하고, 상기 실시예 4와 동일한 방법으로 화합물 D3을 제조하였다(수율 90%).Except for using dichloromethane as a solvent, compound D3 was prepared in the same manner as in Example 4 (yield: 90%).
용매로서 CHCl3를 사용하는 것을 제외하고, 상기 실시예 4와 동일한 방법으로 화합물 D3을 제조하였다(수율 90%).Except for using CHCl 3 as a solvent, compound D3 was prepared in the same manner as in Example 4 (yield: 90%).
용매로서 CH3CN를 사용하는 것을 제외하고, 상기 실시예 4와 동일한 방법으로 화합물 D3을 제조하였다(수율 70%).Compound D3 was prepared in the same manner as in Example 4, except that CH 3 CN was used as a solvent (yield: 70%).
용매로서 테트라하이드로퓨란을 사용하는 것을 제외하고, 상기 실시예 4와 동일한 방법으로 화합물 D3을 제조하였다(수율 56%).Except for using tetrahydrofuran as a solvent, compound D3 was prepared in the same manner as in Example 4 (yield: 56%).
용매로서 톨루엔을 사용하는 것을 제외하고, 상기 실시예 4와 동일한 방법으로 화합물 D3을 제조하였다(수율 73%).Except for using toluene as a solvent, compound D3 was prepared in the same manner as in Example 4 (yield: 73%).
합성 시약으로서 FeCl3를 사용하는 것을 제외하고, 상기 실시예 4와 동일한 방법으로 화합물 D3을 제조하였다(수율 67%).Compound D3 was prepared in the same manner as in Example 4, except that FeCl 3 was used as a synthetic reagent (yield: 67%).
합성 시약으로서 TiCl4를 사용하는 것을 제외하고, 상기 실시예 4와 동일한 방법으로 화합물 D3을 제조하였다(수율 73%).Compound D3 was prepared in the same manner as in Example 4, except that TiCl 4 was used as a synthesis reagent (yield: 73%).
합성 시약으로서 InCl3를 사용하는 것을 제외하고, 상기 실시예 4와 동일한 방법으로 화합물 D3을 제조하였다(수율 80%).Compound D3 was prepared in the same manner as in Example 4, except that InCl 3 was used as a synthesis reagent (yield: 80%).
합성 시약으로서 트리메틸실릴브로마이드를 사용하는 것을 제외하고, 상기 실시예 1과 동일한 방법으로 화합물 D4(4'-Bromo-1-methyl-6'-(trifluoromethyl)spiro[indoline-3,2'-piperidin]-2-one)를 제조하였다(수율 92%). R f = 0.5 (EtOAc/Hexane = 1/4). 1 H NMR (500 MHz, CDCl3): δ 7.36-7.32 (m, 2H), 7.10 (t, J = 7.7 Hz, 1H), 6.82 (d, J = 7.5 Hz, 1H), 4.97-4.91 (m, 1H), 4.52-4.48 (m, 1H), 3.16 (s, 3H), 2.62-2.60 (m, 1H), 2.29-2.27 (m, 2H), 2.09 (q, J = 12.2 Hz, 1H), 1.94 (bs, 1H). 13 C NMR (125 MHz, CDCl3): δ 178.1, 142.8, 130.2, 130.0, 125.0 (C-F, q, 1 J CF = 277.7 Hz), 124.0, 123.5, 108.5, 61.4, 52.8 (C-F, q, 2 J CF = 29.6 Hz), 43.2, 41.1, 35.3, 26.0.Compound D4 (4'-Bromo-1-methyl-6'-(trifluoromethyl)spiro[indoline-3,2'-piperidin] in the same manner as in Example 1, except for using trimethylsilylbromide as a synthesis reagent. -2-one) was prepared (yield: 92%). R f = 0.5 (EtOAc/Hexane = 1/4). 1 H NMR (500 MHz, CDCl 3 ): δ 7.36-7.32 (m, 2H), 7.10 (t, J = 7.7 Hz, 1H), 6.82 (d, J = 7.5 Hz, 1H), 4.97-4.91 (m , 1H), 4.52–4.48 (m, 1H), 3.16 (s, 3H), 2.62–2.60 (m, 1H), 2.29–2.27 (m, 2H), 2.09 (q, J = 12.2 Hz, 1H), 1.94 (bs, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 178.1, 142.8, 130.2, 130.0, 125.0 (CF, q, 1 J CF = 277.7 Hz), 124.0, 123.5, 108.5, 61.4, 52.8 (CF, q, 2 J CF = 29.6 Hz), 43.2, 41.1, 35.3, 26.0.
[화합물 D4][Compound D4]
합성 시약으로서 트리메틸실릴아이오디드를 사용하는 것을 제외하고, 상기 실시예 1과 동일한 방법으로 화합물 D5(4'-Iodo-1-methyl-6'-(trifluoromethyl)spiro[indoline-3,2'-piperidin]-2-one)를 제조하였다(수율 80%). R f = 0.5 (EtOAc/Hexane = 1/2). Mp 246-247 °C; 1 H NMR (500 MHz, CDCl3): δ 7.36-7.31 (m, 2H), 7.10 (td, J = 7.5 Hz, 1.0 Hz, 1H), 6.81 (d, J = 7.5 Hz, 1H), 5.04-4.98 (m, 1H), 4.54-4.48 (m, 1H), 3.16 (s, 3H), 2.71-2.67 (m, 1H), 2.47 (t, J = 13.0 Hz, 1H), 2.38-2.34 (m, 1H), 2.27 (q, J = 12.3 Hz, 1H), 2.04 (bs, 1H). 13 C NMR (125 MHz, CDCl3): δ 178.2, 142.8, 130.2, 130.0, 125.0 (C-F, q, 1 J CF = 277.8 Hz), 124.0, 123.4, 108.5, 61.8, 53.4 (C-F, q, 2 J CF = 29.3 Hz), 45.4, 37.1, 26.0, 16.0. IR: v 3334, 2928, 2360, 1612, 1701, 1469, 1144, 1123, 1095, 581 cm1; HRMS (EI) m/z: [M]+ Calcd. for C14H14F3IN2O 410.0103; Found 410.0101.Compound D5 (4'-Iodo-1-methyl-6'-(trifluoromethyl)spiro[indoline-3,2'-piperidin ]-2-one) was prepared (yield: 80%). R f = 0.5 (EtOAc/Hexane = 1/2). Mp 246-247 °C; 1H NMR (500 MHz, CDCl 3 ): δ 7.36-7.31 (m, 2H), 7.10 (td, J = 7.5 Hz, 1.0 Hz, 1H), 6.81 (d, J = 7.5 Hz, 1H), 5.04- 4.98 (m, 1H), 4.54-4.48 (m, 1H), 3.16 (s, 3H), 2.71-2.67 (m, 1H), 2.47 (t, J = 13.0 Hz, 1H), 2.38-2.34 (m, 1H), 2.27 (q, J = 12.3 Hz, 1H), 2.04 (bs, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 178.2, 142.8, 130.2, 130.0, 125.0 (CF, q, 1 J CF = 277.8 Hz), 124.0, 123.4, 108.5, 61.8, 53.4 (CF, q, 2 J CF = 29.3 Hz), 45.4, 37.1, 26.0, 16.0. IR : v 3334, 2928, 2360, 1612, 1701, 1469, 1144, 1123, 1095, 581 cm 1 ; HRMS (EI) m/z: [M] + Calcd. for C 14 H 14 F 3 IN 2 O 410.0103; Found 410.0101.
[화합물 D5][Compound D5]
1.2. 화합물 A, C 및 합성 시약에 따른 합성 결과 1.2. Synthesis results according to compounds A, C and synthetic reagents
상기 화합물 A1 대신 하기 화합물 A2를 사용하는 것을 제외하고, 상기 실시예 4와 동일한 방법으로 화합물 D6(4'-Chloro-6'-(trifluoromethyl)spiro[indoline-3,2'-piperidin]-2-one)을 제조하였다(수율 45%). R f = 0.5 (EtOAc/Hexane = 1/2). Mp 204-205 °C; 1 H NMR (500 MHz, CDCl3): δ 8.05 (s, 1H), 7.36 (d, J = 7.5 Hz, 1H), 7.28 (td, J = 7.8 Hz, 1.0 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 4.86-4.80 (m, 1H), 4.50-4.43 (m, 1H), 2.54-2.49 (m, 1H), 2.27-2.22 (m, 1H), 2.11 (t, J = 12.8 Hz, 1H), 1.93 (q, J = 12.0 Hz, 1H). 13 C NMR (125 MHz, CDCl3): δ 180.4, 139.8, 130.8, 129.9, 125.1 (C-F, q, 1 J CF = 277.8 Hz), 124.5, 123.5, 110.2, 61.2, 52.3 (C-F, q, 2 J CF = 29.7 Hz), 50.5, 42.2, 34.5. IR: v 3341, 3184, 2923, 1699, 1624, 1476, 1277, 1197, 1146, 682 cm1; HRMS (EI) m/z: [M]+ Calcd. for C13H12ClF3N2O 304.0590; Found 304.0592.Compound D6 (4'-Chloro-6'-(trifluoromethyl)spiro[indoline-3,2'-piperidin]-2- one) was prepared (yield 45%). R f = 0.5 (EtOAc/Hexane = 1/2). Mp 204-205 °C; 1H NMR (500 MHz, CDCl 3 ): δ 8.05 (s, 1H), 7.36 (d, J = 7.5 Hz, 1H), 7.28 (td, J = 7.8 Hz, 1.0 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 4.86-4.80 (m, 1H), 4.50-4.43 (m, 1H), 2.54-2.49 (m, 1H), 2.27-2.22 (m, 1H), 2.11 (t, J = 12.8 Hz, 1H), 1.93 (q, J = 12.0 Hz, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 180.4, 139.8, 130.8, 129.9, 125.1 (CF, q, 1 J CF = 277.8 Hz), 124.5, 123.5, 110.2, 61.2, 52.3 (CF, q, 2 J CF = 29.7 Hz), 50.5, 42.2, 34.5. IR : v 3341, 3184, 2923, 1699, 1624, 1476, 1277, 1197, 1146, 682 cm 1 ; HRMS (EI) m/z: [M] + Calcd. for C 13 H 12 ClF 3 N 2 O 304.0590; Found 304.0592.
[화합물 A2][Compound A2]
[화합물 D6][Compound D6]
상기 화합물 A1 대신 상기 화합물 A2를 사용하는 것을 제외하고, 상기 실시예 14와 동일한 방법으로 화합물 D7(4'-Iodo-6'-(trifluoromethyl)spiro[indoline-3,2'-piperidin]-2-one)을 제조하였다(수율 41%). R f = 0.5 (EtOAc/Hexane = 1/2). Mp 221-222 °C; 1 H NMR (500 MHz, CDCl3): δ 8.02 (s, 1H), 7.36 (d, J = 7.5 Hz, 1H), 7.27 (td, J = 7.9 Hz, 1.2 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 5.01-4.94 (m, 1H), 4.52-4.45 (m, 1H), 2.71-2.67 (m, 1H), 2.27-2.22 (m, 1H), 2.51-2.42 (m, 2H), 2.27 (q, J = 12.3 Hz, 1H). 13 C NMR (125 MHz, CDCl3): δ 180.4, 139.7, 130.7, 129.9, 125.1 (C-F, q, 1 J CF = 277.8 Hz), 124.4, 123.5, 110.2, 62.1, 53.4 (CF, q, 2 J CF = 29.4 Hz), 45.2, 37.1, 15.6. IR: v 3342, 3156, 2846, 1701, 1621, 1474, 1274, 1200, 1141, 571 cm1 ;HRMS (EI) m/z: [M]+ Calcd. for C13H12F3N2OI 395.9946; Found 395.9943.Compound D7 (4'-Iodo-6'-(trifluoromethyl)spiro[indoline-3,2'-piperidin]-2- one) was prepared (yield 41%). R f = 0.5 (EtOAc/Hexane = 1/2). Mp 221-222 °C; 1H NMR (500 MHz, CDCl 3 ): δ 8.02 (s, 1H), 7.36 (d, J = 7.5 Hz, 1H), 7.27 (td, J = 7.9 Hz, 1.2 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 5.01-4.94 (m, 1H), 4.52-4.45 (m, 1H), 2.71-2.67 (m, 1H), 2.27-2.22 (m, 1H), 2.51–2.42 (m, 2H), 2.27 (q, J = 12.3 Hz, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 180.4, 139.7, 130.7, 129.9, 125.1 (CF, q, 1 J CF = 277.8 Hz), 124.4, 123.5, 110.2, 62.1, 53.4 (CF, q, 2 J CF = 29.4 Hz), 45.2, 37.1, 15.6. IR : v 3342, 3156, 2846, 1701, 1621, 1474, 1274, 1200, 1141, 571 cm 1 ; HRMS (EI) m/z: [M] + Calcd. for C 13 H 12 F 3 N 2 OI 395.9946; Found 395.9943.
[화합물 D7][Compound D7]
상기 화합물 A1 대신 하기 화합물 A3을 사용하는 것을 제외하고, 상기 실시예 4와 동일한 방법으로 화합물 D8(4'-Chloro-7-fluoro-1-methyl-6'-(trifluoromethyl)spiro[indoline-3,2'-piperidin]-2-one)을 제조하였다(수율 82%). R f = 0.5 (EtOAc/Hexane = 1/4). Mp 116-117 °C; 1 H NMR (500 MHz, CDCl3): δ 7.15 (dd, J = 6.8 Hz, 1.8 Hz, 1H), 7.08-7.01 (m, 2H), 4.86-4.79 (m, 1H), 4.50-4.43 (m, 1H), 3.37 (d, J = 2.5 Hz, 3H), 2.53-2.48 (m, 1H), 2.19-2.15 (m,1H), 2.06 (t, J = 12.5 Hz, 1H), 1.95 (bs, 1H), 1.90 (q, J = 12.0 Hz, 1H). 13 C NMR (125 MHz, CDCl3): δ 177.7, 147.5 (C-F, d, 1 J CF = 243.1 Hz), 132.9, 129.4 (C-F, d, 2 J CF = 8.4 Hz), 125.0 (C-F, q, 1 J CF = 277.5 Hz), 124.0 (C-F, d, 3 J CF = 5.7 Hz), 119.8, 117.8 (C-F, d, 2 J CF = 19.0 Hz), 61.0, 52.2 (C-F, q, 2 J CF = 29.7 Hz), 50.3 (C-F, d, 3 J CF = 4.6 Hz), 42.3, 34.4, 28.5 (C-F, d, 4 J CF = 5.4 Hz). IR: v 3309, 2922, 1706, 1631, 1481, 1275, 1238,1149, 1132, 731 cm1; HRMS (EI) m/z: [M]+ Calcd. for C14H13ClF4N2O 336.0653; Found 336.0653.Compound D8 (4'-Chloro-7-fluoro-1-methyl-6'-(trifluoromethyl)spiro[indoline-3, 2'-piperidin] -2-one) was prepared (yield: 82%). R f = 0.5 (EtOAc/Hexane = 1/4). Mp 116-117 °C; 1 H NMR (500 MHz, CDCl 3 ): δ 7.15 (dd, J = 6.8 Hz, 1.8 Hz, 1H), 7.08-7.01 (m, 2H), 4.86-4.79 (m, 1H), 4.50-4.43 (m , 1H), 3.37 (d, J = 2.5 Hz, 3H), 2.53-2.48 (m, 1H), 2.19-2.15 (m, 1H), 2.06 (t, J = 12.5 Hz, 1H), 1.95 (bs, 1H), 1.90 (q, J = 12.0 Hz, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 177.7, 147.5 (CF, d, 1 J CF = 243.1 Hz), 132.9, 129.4 (CF, d, 2 J CF = 8.4 Hz), 125.0 (CF, q, 1 J CF = 277.5 Hz), 124.0 (CF, d, 3 J CF = 5.7 Hz), 119.8, 117.8 (CF, d, 2 J CF = 19.0 Hz), 61.0, 52.2 (CF, q, 2 J CF = 29.7 Hz) ), 50.3 (CF, d, 3 J CF = 4.6 Hz), 42.3, 34.4, 28.5 (CF, d, 4 J CF = 5.4 Hz). IR : v 3309, 2922, 1706, 1631, 1481, 1275, 1238, 1149, 1132, 731 cm 1 ; HRMS (EI) m/z: [M] + Calcd. for C 14 H 13 ClF 4 N 2 O 336.0653; Found 336.0653.
[화합물 A3][Compound A3]
[화합물 D8][Compound D8]
상기 화합물 A1 대신 상기 화합물 A3을 사용하는 것을 제외하고, 상기 실시예 14와 동일한 방법으로 화합물 D9(7-Fluoro-4'-iodo-1-methyl-6'-(trifluoromethyl)spiro[indoline-3,2'-piperidin]-2-one)를 제조하였다(수율 83%). R f = 0.5 (EtOAc/Hexane = 1/4). Mp 149-150 °C; 1 H NMR (500 MHz, CDCl3): δ 7.15 (dd, J = 7.0 Hz, 1.5 Hz, 1H), 7.07-7.00 (m, 2H), 5.00-4.93 (m, 1H), 4.52-4.45 (m, 1H), 3.36 (d, J = 2.5 Hz, 3H), 2.70-2.66 (m, 1H), 2.43 (t, J = 12.8Hz, 1H), 2.38-2.34 (m, 1H), 2.25 (q, J = 12.2 Hz, 1H), 2.04 (bs, 1H). 13 C NMR (125 MHz, CDCl3): δ 177.7, 147.5 (C-F, d, 1 J CF = 243.1 Hz), 132.8, 129.3 (C-F, d, 2 J CF = 8.6 Hz), 124.5 (C-F, q, 1 J CF = 277.8 Hz), 124.0(C-F, d, 3 J CF = 6.1 Hz), 119.7 (C-F, d, 3J CF = 6.8 Hz), 117.8 (C-F, d, 2 J CF = 19.0 Hz), 61.8, 53.3 (C-F, q, 2 J CF= 29.4 Hz), 45.4, 37.0, 28.5 (C-F, d, 4 J CF = 5.5 Hz), 15.2. IR: v 3334, 2958, 1709, 1630, 1485, 1275, 1144, 1123,1040, 558 cm1; HRMS (EI) m/z: [M]+ Calcd. for C14H13F4N2OI 428.0009; Found 428.0009.Compound D9 (7-Fluoro-4'-iodo-1-methyl-6'-(trifluoromethyl)spiro[indoline-3, 2'-piperidin] -2-one) was prepared (yield: 83%). R f = 0.5 (EtOAc/Hexane = 1/4). Mp 149-150 °C; 1 H NMR (500 MHz, CDCl 3 ): δ 7.15 (dd, J = 7.0 Hz, 1.5 Hz, 1H), 7.07-7.00 (m, 2H), 5.00-4.93 (m, 1H), 4.52-4.45 (m , 1H), 3.36 (d, J = 2.5 Hz, 3H), 2.70–2.66 (m, 1H), 2.43 (t, J = 12.8 Hz, 1H), 2.38–2.34 (m, 1H), 2.25 (q, J = 12.2 Hz, 1H), 2.04 (bs, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 177.7, 147.5 (CF, d, 1 J CF = 243.1 Hz), 132.8, 129.3 (CF, d, 2 J CF = 8.6 Hz), 124.5 (CF, q, 1 J CF = 277.8 Hz), 124.0 (CF, d, 3 J CF = 6.1 Hz), 119.7 (CF, d, 3 J CF = 6.8 Hz), 117.8 (CF, d, 2 J CF = 19.0 Hz), 61.8, 53.3 (CF, q, 2 J CF = 29.4 Hz), 45.4, 37.0, 28.5 (CF, d, 4 J CF = 5.5 Hz), 15.2. IR : v 3334, 2958, 1709, 1630, 1485, 1275, 1144, 1123,1040, 558 cm 1 ; HRMS (EI) m/z: [M] + Calcd. for C 14 H 13 F 4 N 2 OI 428.0009; Found 428.0009.
[화합물 D9][Compound D9]
상기 화합물 A1 대신 하기 화합물 A4를 사용하는 것을 제외하고, 상기 실시예 4와 동일한 방법으로 화합물 D10(4',5-Dichloro-1-methyl-6'-(trifluoromethyl)spiro[indoline-3,2'-piperidin]-2-one)을 제조하였다(수율 71%). R f = 0.5 (EtOAc/Hexane = 1/4). Mp 202-203 °C; 1 H NMR (500 MHz, CDCl3): δ 7.34 (d, J = 2.0 Hz, 1H), 7.29 (dd, J =8.2 Hz, 1.7 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 4.98-4.92 (m, 1H), 4.49-4.46 (m, 1H), 3.14 (s, 3H), 2.68 (d, J =12.5 Hz, 1H), 2.43 (t, J = 13.0 Hz, 1H), 2.37-2.34 (m, 1H), 2.24 (q, J = 12.3 Hz, 1H). 13 C NMR (125 MHz, CDCl3): δ 177.7, 141.3, 131.8, 129.9, 129.0, 125.1 (C-F, q, 1 J CF = 277.6 Hz), 124.7, 109.5, 61.0, 52.3 (C-F, q, 2 J CF = 29.7 Hz), 50.2, 42.2, 34.4, 26.2. IR: v 3335, 2936, 1701, 1613, 1493, 1343, 1165, 1151, 816, 630 cm1; HRMS (EI) m/z: [M]+ Calcd. for C14H13Cl2F3N2O 352.0357; Found 352.0360. Compound D10 (4',5-Dichloro-1-methyl-6'-(trifluoromethyl)spiro[indoline-3,2' in the same manner as in Example 4, except that Compound A4 was used instead of Compound A1. -piperidin]-2-one) was prepared (yield: 71%). R f = 0.5 (EtOAc/Hexane = 1/4). Mp 202-203 °C; 1H NMR (500 MHz, CDCl 3 ): δ 7.34 (d, J = 2.0 Hz, 1H), 7.29 (dd, J = 8.2 Hz, 1.7 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H) , 4.98–4.92 (m, 1H), 4.49–4.46 (m, 1H), 3.14 (s, 3H), 2.68 (d, J = 12.5 Hz, 1H), 2.43 (t, J = 13.0 Hz, 1H), 2.37–2.34 (m, 1H), 2.24 (q, J = 12.3 Hz, 1H). 13 C NMR (125 MHz, CDCl3): δ 177.7, 141.3, 131.8, 129.9, 129.0, 125.1 (CF, q, 1 J CF = 277.6 Hz), 124.7, 109.5, 61.0, 52.3 (CF, q, 2 J CF = 29.7 Hz), 50.2, 42.2, 34.4, 26.2. IR : v 3335, 2936, 1701, 1613, 1493, 1343, 1165, 1151, 816, 630 cm 1 ; HRMS (EI) m/z: [M] + Calcd. for C 14 H 13 C 12 F 3 N 2 O 352.0357; Found 352.0360.
[화합물 A4][Compound A4]
[화합물 D10][Compound D10]
상기 화합물 A1 대신 상기 화합물 A4를 사용하는 것을 제외하고, 상기 실시예 14와 동일한 방법으로 화합물 D11(5-Chloro-4'-iodo-1-methyl-6'-(trifluoromethyl)spiro[indoline-3,2'-piperidin]-2-one)을 제조하였다(수율 77%). R f = 0.5 (EtOAc/Hexane = 1/4). Mp 206-207 °C; 1 H NMR (500 MHz, CDCl3): δ 7.36-7.31 (m, 1H), 7.10 (t, J = 7.5 Hz, 1.0 Hz, 1H), 6.81 (d, J = 7.5 Hz, 1H), 5.04-4.98 (m, 1H), 4.54-4.48 (m, 1H), 3.16 (s, 3H), 2.71-2.67 (m, 1H), 2.47 (t, J = 13.0 Hz, 1H), 2.38-2.34 (m, 1H), 2.24 (q, J = 12.3 Hz, 1H), 2.08 (bs, 1H). 13 C NMR (125 MHz, CDCl3): δ 177.7, 141.3, 131.7, 129.8, 128.9, 124.6, 124.3 (C-F, q, 1 J CF = 277.8 Hz), 109.5, 61.9, 53.4 (C-F, q, 2 J CF =29.4 Hz), 45.2, 37.0, 26.2, 15.1. IR: v 3334, 2930, 1702, 1612, 1493, 1268, 1165, 1093, 811, 563 cm1; HRMS(EI) m/z: [M]+ Calcd. for C14H13ClF3N2OI 443.9713; Found 443.9716.Compound D11 (5-Chloro-4'-iodo-1-methyl-6'-(trifluoromethyl)spiro[indoline-3, 2'-piperidin] -2-one) was prepared (yield: 77%). R f = 0.5 (EtOAc/Hexane = 1/4). Mp 206-207 °C; 1H NMR (500 MHz, CDCl 3 ): δ 7.36-7.31 (m, 1H), 7.10 (t, J = 7.5 Hz, 1.0 Hz, 1H), 6.81 (d, J = 7.5 Hz, 1H), 5.04- 4.98 (m, 1H), 4.54-4.48 (m, 1H), 3.16 (s, 3H), 2.71-2.67 (m, 1H), 2.47 (t, J = 13.0 Hz, 1H), 2.38-2.34 (m, 1H), 2.24 (q, J = 12.3 Hz, 1H), 2.08 (bs, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 177.7, 141.3, 131.7, 129.8, 128.9, 124.6, 124.3 (CF, q, 1 J CF = 277.8 Hz), 109.5, 61.9, 53.4 (CF, q, 2 J CF =29.4 Hz), 45.2, 37.0, 26.2, 15.1. IR : v 3334, 2930, 1702, 1612, 1493, 1268, 1165, 1093, 811, 563 cm 1 ; HRMS (EI) m/z: [M] + Calcd. for C 14 H 13 ClF 3 N 2 OI 443.9713; Found 443.9716.
[화합물 D11][Compound D11]
상기 화합물 A1 대신 하기 화합물 A5를 사용하는 것을 제외하고, 상기 실시예 4와 동일한 방법으로 화합물 D12(5-Bromo-4'-chloro-1-methyl-6'-(trifluoromethyl)spiro[indoline-3,2'-piperidin]-2-one)를 제조하였다(수율 80%). R f = 0.5 (EtOAc/Hexane = 1/4). Mp 206-207 °C; 1 H NMR (500 MHz, CDCl3): δ 7.48 (s, 1H), 7.46 (dd, J = 8.2 Hz, 1.7 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 4.85-4.79 (m, 1H), 4.47-4.44 (m, 1H), 3.14 (s, 3H), 2.51 (dd, J = 12.5 Hz, 2.0 Hz, 1H), 2.18-2.15 (m, 1H), 2.07 (t, J = 12.5 Hz, 1H), 1.90 (q, J = 12.0 Hz, 1H). 13 C NMR (125 MHz, CDCl3): δ 177.6, 141.8, 132.8, 132.1, 127.4, 125.1 (C-F, q, 1 J CF = 277.5 Hz), 116.1, 110.0, 61.0, 52.3 (C-F, q, 2 J CF = 29.7 Hz), 50.2, 42.2, 34.4, 26.2. IR: v 3332, 2936, 1702, 1609, 1490, 1270, 1166, 1150, 812, 630 cm1; HRMS (EI) m/z: [M]+ Calcd. for C14H13BrClF3N2O 397.9830; Found 397.9824.Compound D12 (5-Bromo-4'-chloro-1-methyl-6'-(trifluoromethyl)spiro[indoline-3, 2'-piperidin] -2-one) was prepared (yield: 80%). R f = 0.5 (EtOAc/Hexane = 1/4). Mp 206-207 °C; 1H NMR (500 MHz, CDCl3): δ 7.48 (s, 1H), 7.46 (dd, J = 8.2 Hz, 1.7 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 4.85-4.79 (m , 1H), 4.47–4.44 (m, 1H), 3.14 (s, 3H), 2.51 (dd, J = 12.5 Hz, 2.0 Hz, 1H), 2.18–2.15 (m, 1H), 2.07 (t, J = 12.5 Hz). 12.5 Hz, 1H), 1.90 (q, J = 12.0 Hz, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 177.6, 141.8, 132.8, 132.1, 127.4, 125.1 (CF, q, 1 J CF = 277.5 Hz), 116.1, 110.0, 61.0, 52.3 (CF, q, 2 J CF = 29.7 Hz), 50.2, 42.2, 34.4, 26.2. IR : v 3332, 2936, 1702, 1609, 1490, 1270, 1166, 1150, 812, 630 cm 1 ; HRMS (EI) m/z: [M] + Calcd. for C 14 H 13 BrClF 3 N 2 O 397.9830; Found 397.9824.
[화합물 A5][Compound A5]
[화합물 D12][Compound D12]
상기 화합물 A1 대신 상기 화합물 A5를 사용하는 것을 제외하고, 상기 실시예 14와 동일한 방법으로 화합물 D13(5-Bromo-4'-iodo-1-methyl-6'-(trifluoromethyl)spiro[indoline-3,2'-piperidin]-2-one)을 제조하였다(수율 76%). R f = 0.5 (EtOAc/Hexane = 1/4). Mp 214-215 °C; 1 H NMR (500 MHz, CDCl3): δ 7.48 (d, J = 1.5 Hz, 1H), 7.44 (dd, J =8.3 Hz, 1.8 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H), 4.98-4.92 (m, 1H), 4.49-4.44 (m, 1H), 3.14 (s, 3H), 2.68 (d, J =12.5 Hz, 1H), 2.44 (t, J = 12.7 Hz, 1H), 2.37-2.33 (m, 1H), 2.24 (q, J = 12.3 Hz, 1H), 2.08 (bs, 1H). 13 C NMR(125 MHz, CDCl3): δ 177.6, 141.8, 132.7, 132.0, 127.3, 124.5 (C-F, q, 1 J CF = 277.9 Hz), 116.1, 110.0, 61.8, 53.4(C-F, q, 2 J CF = 29.5 Hz), 45.2, 37.0, 26.1, 15.0. IR: v 3333, 2917, 1702, 1608, 1490, 1267, 1162, 1091, 809, 586cm1; HRMS (EI) m/z: [M]+ Calcd. for C14H13BrF3N2OI 487.9208; Found 487.9211.Compound D13 (5-Bromo-4'-iodo-1-methyl-6'-(trifluoromethyl)spiro[indoline-3, 2'-piperidin] -2-one) was prepared (yield: 76%). R f = 0.5 (EtOAc/Hexane = 1/4). Mp 214-215 °C; 1H NMR (500 MHz, CDCl 3 ): δ 7.48 (d, J = 1.5 Hz, 1H), 7.44 (dd, J = 8.3 Hz, 1.8 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H) , 4.98–4.92 (m, 1H), 4.49–4.44 (m, 1H), 3.14 (s, 3H), 2.68 (d, J = 12.5 Hz, 1H), 2.44 (t, J = 12.7 Hz, 1H), 2.37–2.33 (m, 1H), 2.24 (q, J = 12.3 Hz, 1H), 2.08 (bs, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 177.6, 141.8, 132.7, 132.0, 127.3, 124.5 (CF, q, 1 J CF = 277.9 Hz), 116.1, 110.0, 61.8, 53.4 (CF, q, 2 J CF = 29.5 Hz), 45.2, 37.0, 26.1, 15.0. IR : v 3333, 2917, 1702, 1608, 1490, 1267, 1162, 1091, 809, 586 cm 1 ; HRMS (EI) m/z: [M] + Calcd. for C 14 H 13 BrF 3 N 2 OI 487.9208; Found 487.9211.
[화합물 D13][Compound D13]
상기 화합물 A1 대신 하기 화합물 A6을 사용하는 것을 제외하고, 상기 실시예 4와 동일한 방법으로 화합물 D14(4'-Chloro-5-iodo-1-methyl-6'-(trifluoromethyl)spiro[indoline-3,2'-piperidin]-2-one)을 제조하였다(수율 77%). R f = 0.5 (EtOAc/Hexane = 1/4). Mp 237-238 °C; 1 H NMR (500 MHz, CDCl3): δ 7.65 (dd, J = 7.8 Hz, 1.7 Hz, 2H), 6.60 (d, J = 9.0 Hz, 1H), 4.84-4.77 (m, 1H), 4.48-4.41 (m, 1H), 3.13 (s, 3H), 2.52-2.48 (m, 1H), 2.18-2.14 (m, 1H), 2.07 (t, J = 12.5 Hz, 1H), 1.95 (bs, 1H), 1.90 (q, J = 12.2 Hz, 1H). 13 C NMR (125 MHz, CDCl3): δ 177.4, 142.5, 138.7, 132.9, 132.3, 125.0 (C-F, q, 1 J CF = 278.0 Hz), 110.5, 85.8, 60.8, 52.2 (C-F, q, 2 J CF = 29.9 Hz), 50.2, 42.2, 34.4, 26.1. IR: v 3327, 2922, 1701, 1603, 1488, 1271, 1166, 1121, 809, 592 cm1; HRMS (EI) m/z: [M]+ Calcd. for C14H13ClF3N2OI 443.9713; Found 443.9716.Compound D14 (4'-Chloro-5-iodo-1-methyl-6'-(trifluoromethyl)spiro[indoline-3, 2'-piperidin] -2-one) was prepared (yield: 77%). R f = 0.5 (EtOAc/Hexane = 1/4). Mp 237-238 °C; 1 H NMR (500 MHz, CDCl 3 ): δ 7.65 (dd, J = 7.8 Hz, 1.7 Hz, 2H), 6.60 (d, J = 9.0 Hz, 1H), 4.84-4.77 (m, 1H), 4.48- 4.41 (m, 1H), 3.13 (s, 3H), 2.52-2.48 (m, 1H), 2.18-2.14 (m, 1H), 2.07 (t, J = 12.5 Hz, 1H), 1.95 (bs, 1H) , 1.90 (q, J = 12.2 Hz, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 177.4, 142.5, 138.7, 132.9, 132.3, 125.0 (CF, q, 1 J CF = 278.0 Hz), 110.5, 85.8, 60.8, 52.2 (CF, q, 2 J CF = 29.9 Hz), 50.2, 42.2, 34.4, 26.1. IR : v 3327, 2922, 1701, 1603, 1488, 1271, 1166, 1121, 809, 592 cm 1 ; HRMS (EI) m/z: [M] + Calcd. for C 14 H 13 ClF 3 N 2 OI 443.9713; Found 443.9716.
[화합물 A6] [Compound A6]
[화합물 D14][Compound D14]
상기 화합물 A1 대신 상기 화합물 A6을 사용하는 것을 제외하고 상기 실시예 14와 동일한 방법으로 화합물 D15(4',5-Diiodo-1-methyl-6'-(trifluoromethyl)spiro[indoline-3,2'-piperidin]-2-one)를 제조하였다(수율 72%). R f = 0.5(EtOAc/Hexane = 1/4). Mp 244-245 °C; 1 H NMR (500 MHz, CDCl3): δ 7.65-7.63 (m, 2H), 6.59 (d, J = 8.5 Hz, 1H), 4.98-4.91 (m, 1H), 4.50-4.43 (m, 1H), 3.13 (s, 3H), 2.70-2.66 (m, 1H), 2.43 (t, J = 12.8 Hz, 1H), 2.36-2.33 (m, 1H), 2.24 (q, J = 12.2 Hz, 1H), 2.0 (bs, 1H). 13 C NMR (125 MHz, CDCl3): δ 177.4, 142.4, 138.6, 132.8, 132.3, 124.5 (C-F, q, 1 J CF = 278.0 Hz), 110.4, 85.8, 61.6, 53.4 (C-F, q, 2 J CF = 29.4 Hz), 45.2, 37.0, 26.0, 15.0. IR: v 3325, 2931, 1702, 1602, 1488, 1271, 1164, 1118, 621, 575 cm1; HRMS (EI) m/z: [M]+ Calcd. For C14H13I2F3N2O 535.9070; Found 535.9067.Compound D15 (4',5-Diiodo-1-methyl-6'-(trifluoromethyl)spiro[indoline-3,2'- piperidin]-2-one) was prepared (yield: 72%). R f = 0.5 (EtOAc/Hexane = 1/4). Mp 244-245 °C; 1 H NMR (500 MHz, CDCl 3 ): δ 7.65-7.63 (m, 2H), 6.59 (d, J = 8.5 Hz, 1H), 4.98-4.91 (m, 1H), 4.50-4.43 (m, 1H) , 3.13 (s, 3H), 2.70–2.66 (m, 1H), 2.43 (t, J = 12.8 Hz, 1H), 2.36–2.33 (m, 1H), 2.24 (q, J = 12.2 Hz, 1H), 2.0 (bs, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 177.4, 142.4, 138.6, 132.8, 132.3, 124.5 (CF, q, 1 J CF = 278.0 Hz), 110.4, 85.8, 61.6, 53.4 (CF, q, 2 J CF = 29.4 Hz), 45.2, 37.0, 26.0, 15.0. IR : v 3325, 2931, 1702, 1602, 1488, 1271, 1164, 1118, 621, 575 cm 1 ; HRMS (EI) m/z: [M] + Calcd. For C 14 H 13 I 2 F 3 N 2 O 535.9070; Found 535.9067.
[화합물 D15][Compound D15]
상기 화합물 A1 대신 하기 화합물 A7을 사용하는 것을 제외하고, 상기 실시예 4와 동일한 방법으로 화합물 D16(4'-Chloro-5-methoxy-1-methyl-6'-(trifluoromethyl)spiro[indoline-3,2'-piperidin]-2-one)을 제조하였다(수율 70%). R f = 0.5 (EtOAc/Hexane = 1/2). Mp 182-184 °C; 1 H NMR (500 MHz, CDCl3): δ 6.96 (d, J = 2.5 Hz, 1H), 6.85 (dd, J = 8.0 Hz, 2.5 Hz, 1H), 6.79 (d, J = 8.5 Hz, 1H), 4.88-4.84 (m, 1H), 4.52-4.48 (m, 1H), 3.80 (s, 3H), 3.13 (s, 3H), 2.52-2.49 (m, 1H), 2.18-2.15 (m, 1H), 2.07 (t, J = 12.8 Hz, 1H), 1.91 (q, J = 12.0 Hz, 1H). 13 C NMR (125 MHz, CDCl3): δ 177.9, 156.7, 136.0, 131.4, 125.1 (C-F, q, 1 J CF = 277.5 Hz), 114.6, 110.8, 109.0, 61.3, 56.0, 52.3 (C-F, q, 2 J CF = 29.7 Hz), 50.6, 42.4, 34.5, 26.1. IR: v 3319, 2938, 1690, 1603, 1496, 1278, 1200, 1145, 1119, 804 cm1; HRMS (EI) m/z: [M]+ Calcd. for C15H16ClF3N2O2 348.0852; Found 348.0849.Compound D16 (4'-Chloro-5-methoxy-1-methyl-6'-(trifluoromethyl)spiro[indoline-3, 2'-piperidin] -2-one) was prepared (yield: 70%). R f = 0.5 (EtOAc/Hexane = 1/2). Mp 182-184 °C; 1H NMR (500 MHz, CDCl 3 ): δ 6.96 (d, J = 2.5 Hz, 1H), 6.85 (dd, J = 8.0 Hz, 2.5 Hz, 1H), 6.79 (d, J = 8.5 Hz, 1H) , 4.88-4.84 (m, 1H), 4.52-4.48 (m, 1H), 3.80 (s, 3H), 3.13 (s, 3H), 2.52-2.49 (m, 1H), 2.18-2.15 (m, 1H) , 2.07 (t, J = 12.8 Hz, 1H), 1.91 (q, J = 12.0 Hz, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 177.9, 156.7, 136.0, 131.4, 125.1 (CF, q, 1 J CF = 277.5 Hz), 114.6, 110.8, 109.0, 61.3, 56.0, 52.3 (CF, q, 2J CF = 29.7 Hz), 50.6 , 42.4, 34.5, 26.1. IR : v 3319, 2938, 1690, 1603, 1496, 1278, 1200, 1145, 1119, 804 cm 1 ; HRMS (EI) m/z: [M] + Calcd. for C 15 H 16 ClF 3 N 2 O 2 348.0852; Found 348.0849.
[화합물 A7][Compound A7]
[화합물 D16][Compound D16]
상기 화합물 A1 대신 상기 화합물 A7을 사용하는 것을 제외하고, 상기 실시예 14와 동일한 방법으로 화합물 D17(4'-Iodo-5-methoxy-1-methyl-6'-(trifluoromethyl)spiro[indoline-3,2'-piperidin]-2-one)을 제조하였다(수율 77%). R = = 0.5 (EtOAc/Hexane = 1/2). Mp 206-208 °C; 1 H NMR (500 MHz, CDCl3): δ 6.96 (d, J = 2.5 Hz, 1H), 6.45 (dd, J = 8.3 Hz, 2.8 Hz, 1H), 6.71 (d, J = 8.5 Hz, 1H), 5.04-4.97 (m, 1H), 4.55-4.48 (m, 1H), 3.80 (s, 3H), 3.13 (s, 3H), 2.70-2.66 (m, 1H), 2.44 (t, J = 13.0 Hz, 1H), 2.37-2.33 (m, 1H), 2.26 (q, J = 12.2 Hz, 1H), 2.03 (bs, 1H). 13 C NMR (125 MHz, CDCl3): δ 177.9, 156.6, 136.0, 131.3, 124.6 (C-F, q, 1 J CF = 280.8 Hz), 114.6, 110.7, 108.9, 62.1, 56.0, 53.4 (CF, q, 2 J CF = 29.6 Hz), 45.5, 37.1, 26.0, 16.0. IR: v 3330, 2928, 1695, 1600, 1468, 1287, 1233, 1177, 1114, 568 cm1; HRMS (EI) m/z: [M]+ Calcd. for C15H16F3N2O2I 440.0209; Found 440.0211.Compound D17 (4'-Iodo-5-methoxy-1-methyl-6'-(trifluoromethyl)spiro[indoline-3, 2'-piperidin] -2-one) was prepared (yield: 77%). R = = 0.5 (EtOAc/Hexane = 1/2). Mp 206-208 °C; 1H NMR (500 MHz, CDCl 3 ): δ 6.96 (d, J = 2.5 Hz, 1H), 6.45 (dd, J = 8.3 Hz, 2.8 Hz, 1H), 6.71 (d, J = 8.5 Hz, 1H) , 5.04-4.97 (m, 1H), 4.55-4.48 (m, 1H), 3.80 (s, 3H), 3.13 (s, 3H), 2.70-2.66 (m, 1H), 2.44 (t, J = 13.0 Hz) , 1H), 2.37–2.33 (m, 1H), 2.26 (q, J = 12.2 Hz, 1H), 2.03 (bs, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 177.9, 156.6, 136.0, 131.3, 124.6 (CF, q, 1 J CF = 280.8 Hz), 114.6, 110.7, 108.9 , 62.1, 56.0, 53.4 (CF, q, 2J CF = 29.6 Hz), 45.5, 37.1, 26.0, 16.0. IR : v 3330, 2928, 1695, 1600, 1468, 1287, 1233, 1177, 1114, 568 cm 1 ; HRMS (EI) m/z: [M] + Calcd. for C 15 H 16 F 3 N 2 O 2 I 440.0209; Found 440.0211.
[화합물 D17][Compound D17]
상기 화합물 A1 대신 하기 화합물 A8을 사용하는 것을 제외하고, 상기 실시예 4와 동일한 방법으로 화합물 D18(4'-Chloro-1,5,7-trimethyl-6'-(trifluoromethyl)spiro[indoline-3,2'-piperidin]-2-one)을 제조하였다(수율 73%). R f = 0.5 (EtOAc/Hexane = 1/4). Mp 152-153 °C; 1 H NMR (500 MHz, CDCl3): δ 7.01 (s, 1H), 6.86 (s, 1H), 4.89-4.83 (m, 1H), 4.52-4.45 (m, 1H), 3.40 (s, 3H), 2.51 (s, 4H), 2.28 (s, 3H), 2.14-2.10 (m, 1H), 2.03 (t, J = 12.5 Hz, 1H), 1.89 (q, J = 12.0 Hz, 1H), 1.76 (bs, 1H). 13 C NMR (125 MHz, CDCl3): δ 178.7, 138.0, 134.0, 133.0, 131.0, 125.2 (CF, q, 1 J CF = 277.6 Hz), 122.6, 119.9, 60.3, 52.3 (C-F, q, 2 J CF = 29.6 Hz), 50.9, 42.7, 34.6, 29.3, 20.8, 18.8. IR: v 3319, 2924, 1698, 1606, 1485, 1354, 1328, 1278, 1150, 636 cm1; HRMS (EI+) m/z: [M]+ Calcd for C16H18ClF3N2O 346.1060; Found 346.1061.Compound D18 (4'-Chloro-1,5,7-trimethyl-6'-(trifluoromethyl)spiro[indoline-3, 2'-piperidin] -2-one) was prepared (yield: 73%). R f = 0.5 (EtOAc/Hexane = 1/4). Mp 152-153 °C; 1 H NMR (500 MHz, CDCl 3 ): δ 7.01 (s, 1H), 6.86 (s, 1H), 4.89-4.83 (m, 1H), 4.52-4.45 (m, 1H), 3.40 (s, 3H) , 2.51 (s, 4H), 2.28 (s, 3H), 2.14–2.10 (m, 1H), 2.03 (t, J = 12.5 Hz, 1H), 1.89 (q, J = 12.0 Hz, 1H), 1.76 ( bs, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 178.7, 138.0, 134.0, 133.0, 131.0, 125.2 (CF, q, 1 J CF = 277.6 Hz), 122.6, 119.9, 60.3, 52.3 (CF, q, 2 J CF = 29.6 Hz), 50.9, 42.7, 34.6, 29.3, 20.8, 18.8. IR : v 3319, 2924, 1698, 1606, 1485, 1354, 1328, 1278, 1150, 636 cm 1 ; HRMS (EI+) m/z: [M] + Calcd for C 16 H 18 ClF 3 N 2 O 346.1060; Found 346.1061.
[화합물 A8][Compound A8]
[화합물 D18][Compound D18]
상기 화합물 A1 대신 상기 화합물 A8을 사용하는 것을 제외하고, 상기 실시예 14와 동일한 방법으로 화합물 D19(4'-Iodo-1,5,7-trimethyl-6'-(trifluoromethyl)spiro[indoline-3,2'-piperidin]-2-one)를 제조하였다(수율 75%). R f = 0.5 (EtOAc/Hexane = 1/4). Mp 197-198 °C; 1 H NMR (500 MHz, CDCl3): δ 7.01 (s, 1H), 6.85 (s, 1H), 5.03-4.97 (m, 1H), 4.54-4.48 (m, 1H), 3.40 (s, 3H), 2.69-2.67 (m, 1H), 2.50 (s, 3H), 2.41 (t, J = 13.0 Hz, 1H), 2.33-2.30 (m, 1H), 2.28 (s, 3H), 2.23 (t, J = 12.3 Hz, 1H), 1.97 (bs, 1H). 13 C NMR (125 MHz, CDCl3): δ 178.7, 137.9, 133.9, 133.0, 130.9, 124.7 (C-F, q, 1 J CF = 277.7 Hz), 122.5, 119.8, 61.2, 53.5 (C-F, q, 2 J CF = 29.1 Hz), 45.8, 37.2, 29.2, 20.8, 18.8, 16.4. IR: v 3318, 2921, 1691, 1601, 1483, 1447, 1318, 1274, 1096, 868, 573 cm1; HRMS (EI) m/z: [M]+ Calcd. for C16H18F3N2OI 438.0416; Found 438.0412.Compound D19 (4'-Iodo-1,5,7-trimethyl-6'-(trifluoromethyl)spiro[indoline-3, 2'-piperidin] -2-one) was prepared (yield: 75%). R f = 0.5 (EtOAc/Hexane = 1/4). Mp 197-198 °C; 1 H NMR (500 MHz, CDCl 3 ): δ 7.01 (s, 1H), 6.85 (s, 1H), 5.03-4.97 (m, 1H), 4.54-4.48 (m, 1H), 3.40 (s, 3H) , 2.69–2.67 (m, 1H), 2.50 (s, 3H), 2.41 (t, J = 13.0 Hz, 1H), 2.33–2.30 (m, 1H), 2.28 (s, 3H), 2.23 (t, J = 12.3 Hz, 1H), 1.97 (bs, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 178.7, 137.9, 133.9, 133.0, 130.9, 124.7 (CF, q, 1 J CF = 277.7 Hz), 122.5, 119.8, 61.2, 53.5 (CF, q, 2 J CF = 29.1 Hz), 45.8, 37.2, 29.2, 20.8, 18.8, 16.4. IR : v 3318, 2921, 1691, 1601, 1483, 1447, 1318, 1274, 1096, 868, 573 cm 1 ; HRMS (EI) m/z: [M] + Calcd. for C 16 H 18 F 3 N 2 OI 438.0416; Found 438.0412.
[화합물 D19][Compound D19]
상기 화합물 A1 대신 하기 화합물 A9를 사용하는 것을 제외하고, 상기 실시예 4와 동일한 방법으로 화합물 D20(4'-Chloro-1-methyl-2-oxo-6'-(trifluoromethyl)spiro[indoline-3,2'-piperidine]-5-carbonitrile)을 제조하였다(수율 55%). R f = 0.5 (EtOAc/Hexane = 1/2). Mp 198-199 °C; 1 H NMR (500 MHz, CDCl3): δ 7.67-7.63 (m, 2H), 6.90 (d, J = 8.0 Hz, 1H), 4.81-4.75 (m, 1H), 4.46-4.39 (m, 1H), 3.19 (s, 3H), 2.54-2.50 (m, 1H), 2.19-2.15 (m, 1H), 2.09 (t, J = 12.8 Hz, 1H), 2.00 (bs, 1H), 1.92 (q, J = 12.0 Hz, 1H). 13 C NMR (125 MHz, CDCl3): δ 177.8, 146.6, 135.1, 131.2, 127.6, 124.9 (C-F, q, 1 J CF = 277.5 Hz), 118.5, 109.0, 106.8, 60.5, 52.2 (C-F, q, 2 J CF = 29.9 Hz), 49.7, 42.0, 34.3, 26.3. IR: v 3312, 2941, 2223, 1715, 1617, 1496, 1276, 1178, 1128, 685 cm1; HRMS (EI) m/z: [M]+ Calcd. For C15H13ClF3N3O 343.0699; Found 343.0696. Compound D20 (4'-Chloro-1-methyl-2-oxo-6'-(trifluoromethyl)spiro[indoline-3, 2'-piperidine] -5-carbonitrile) was prepared (yield: 55%). R f = 0.5 (EtOAc/Hexane = 1/2). Mp 198-199 °C; 1 H NMR (500 MHz, CDCl 3 ): δ 7.67-7.63 (m, 2H), 6.90 (d, J = 8.0 Hz, 1H), 4.81-4.75 (m, 1H), 4.46-4.39 (m, 1H) , 3.19 (s, 3H), 2.54–2.50 (m, 1H), 2.19–2.15 (m, 1H), 2.09 (t, J = 12.8 Hz, 1H), 2.00 (bs, 1H), 1.92 (q, J = 12.0 Hz, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 177.8, 146.6, 135.1, 131.2, 127.6, 124.9 (CF, q, 1 J CF = 277.5 Hz), 118.5, 109.0, 106.8, 60.5, 52.2 (CF, q, 2J _ CF = 29.9 Hz), 49.7, 42.0, 34.3, 26.3. IR : v 3312, 2941, 2223, 1715, 1617, 1496, 1276, 1178, 1128, 685 cm 1 ; HRMS (EI) m/z: [M] + Calcd. For C 15 H 13 ClF 3 N 3 O 343.0699; Found 343.0696.
[화합물 A9][Compound A9]
[화합물 D20][Compound D20]
상기 화합물 A1 대신 상기 화합물 A9를 사용하는 것을 제외하고, 상기 실시예 14와 동일한 방법으로 화합물 D21(4'-Iodo-1-methyl-2-oxo-6'-(trifluoromethyl)spiro[indoline-3,2'-piperidine]-5-carbonitrile)을 제조하였다(수율 59%). R f = 0.5 (EtOAc/Hexane = 1/2). Mp 230-233 °C; 1 H NMR (500 MHz, CDCl3): δ 7.66-7.63 (m, 2H), 6.89 (d, J = 8.0 Hz, 1H), 4.95-4.88 (m, 1H), 4.48-4.41 (m, 1H), 3.19 (s, 3H), 2.71-2.67 (m, 1H), 2.45 (t, J = 13.0 Hz, 1H), 2.38-2.34 (m, 1H), 2.26 (q, J = 12.2 Hz, 1H), 2.10 (bs, 1H). 13 C NMR (125 MHz, CDCl3): δ 177.8, 146.5, 135.0, 131.2, 127.7, 124.3 (C-F, q, 1 J CF = 277.8 Hz), 118.5, 109.0, 106.8, 61.4, 53.3 (C-F, q, 2 J CF = 29.5 Hz), 45.0, 36.8, 26.3, 14.0. IR: v 3311, 2916, 2223, 1710, 1616, 1496, 1340, 1141, 1127, 566 cm1; HRMS (EI) m/z: [M]+ Calcd. For C15H13F3N3OI 435.0055; Found 435.0058.Compound D21 (4'-Iodo-1-methyl-2-oxo-6'-(trifluoromethyl)spiro[indoline-3, 2'-piperidine] -5-carbonitrile) was prepared (yield: 59%). R f = 0.5 (EtOAc/Hexane = 1/2). Mp 230-233 °C; 1 H NMR (500 MHz, CDCl 3 ): δ 7.66-7.63 (m, 2H), 6.89 (d, J = 8.0 Hz, 1H), 4.95-4.88 (m, 1H), 4.48-4.41 (m, 1H) , 3.19 (s, 3H), 2.71–2.67 (m, 1H), 2.45 (t, J = 13.0 Hz, 1H), 2.38–2.34 (m, 1H), 2.26 (q, J = 12.2 Hz, 1H), 2.10 (bs, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 177.8, 146.5, 135.0, 131.2, 127.7, 124.3 (CF, q, 1 J CF = 277.8 Hz), 118.5, 109.0, 106.8, 61.4, 53.3 (CF, q, 2 J CF = 29.5 Hz), 45.0, 36.8, 26.3, 14.0. IR : v 3311, 2916, 2223, 1710, 1616, 1496, 1340, 1141, 1127, 566 cm 1 ; HRMS (EI) m/z: [M] + Calcd. For C 15 H 13 F 3 N 3 OI 435.0055; Found 435.0058.
[화합물 D21][Compound D21]
상기 화합물 A1 대신 하기 화합물 A10을 사용하는 것을 제외하고, 상기 실시예 4와 동일한 방법으로 화합물 D22(Methyl 4'-chloro-1-methyl-2-oxo-6'-(trifluoromethyl)spiro[indoline-3,2'-piperidine]-5-carboxylate)를 제조하였다(수율 62%). R f = 0.5 (EtOAc/Hexane= 1/2). Mp 249-250 °C; 1 H NMR (500 MHz, CDCl3): δ 8.08 (dd, J = 8.5 Hz, 1.5 Hz, 1H), 8.02 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 8.5 Hz, 1H), 4.85-4.79 (m, 1H), 4.48-4.42 (m, 1H), 3.91 (s, 3H), 3.19 (s, 3H), 2.54-2.50 (m, 1H), 2.16-2.14 (m, 2H), 2.37-2.34 (m, 1H), 1.93 (q, J = 12.0 Hz, 1H). 13 C NMR (125 MHz, CDCl3): δ 178.4, 166.5, 146.8, 132.6, 130.2, 125.5, 125.4, 125.1 (C-F, q, 1 J CF = 277.6 Hz), 108.2, 60.7, 52.3 (C-F, q, 2 J CF = 29.7 Hz), 52.2, 50.3, 42.1, 34.5, 26.3. IR: v 3337, 2917, 1710, 1617, 1498, 1447, 1300, 1271, 1125, 1092, 630 cm1; HRMS (EI) m/z: [M]+ Calcd. for C16H16ClF3N2O3 376.0802; Found 376.0803.Compound D22 (Methyl 4'-chloro-1-methyl-2-oxo-6'-(trifluoromethyl)spiro[indoline-3 ,2'-piperidine] -5-carboxylate) was prepared (yield: 62%). R f = 0.5 (EtOAc/Hexane=1/2). Mp 249-250 °C; 1 H NMR (500 MHz, CDCl 3 ): δ 8.08 (dd, J = 8.5 Hz, 1.5 Hz, 1H), 8.02 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 8.5 Hz, 1H) , 4.85-4.79 (m, 1H), 4.48-4.42 (m, 1H), 3.91 (s, 3H), 3.19 (s, 3H), 2.54-2.50 (m, 1H), 2.16-2.14 (m, 2H) , 2.37–2.34 (m, 1H), 1.93 (q, J = 12.0 Hz, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 178.4, 166.5, 146.8, 132.6, 130.2, 125.5, 125.4, 125.1 (CF, q, 1 J CF = 277.6 Hz), 108.2, 60.7, 52.3 (CF, q, 2J _ CF = 29.7 Hz), 52.2, 50.3, 42.1, 34.5, 26.3. IR : v 3337, 2917, 1710, 1617, 1498, 1447, 1300, 1271, 1125, 1092, 630 cm 1 ; HRMS (EI) m/z: [M] + Calcd. for C 16 H 16 ClF 3 N 2 O 3 376.0802; Found 376.0803.
[화합물 A10][Compound A10]
[화합물 D22][Compound D22]
상기 화합물 A1 대신 상기 화합물 10을 사용하는 것을 제외하고, 상기 실시예 14와 동일한 방법으로 화합물 D23(Methyl 4'-iodo-1-methyl-2-oxo-6'-(trifluoromethyl)spiro[indoline-3,2'-piperidine]-5-carboxylate)을 제조하였다(수율 75%). R f = 0.5 (EtOAc/Hexane = 1/2). Mp 255-256 °C; 1 H NMR (500 MHz, CDCl3): δ 8.06 (dd, J = 8.3 Hz, 1.7 Hz, 1H), 8.01 (d, J = 2.0 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 4.99-4.93 (m, 1H), 4.50-4.44 (m, 1H), 3.90 (s, 3H), 3.19 (s, 3H), 2.71-2.67 (m, 1H), 2.51 (t, J = 13.0 Hz, 1H), 2.37-2.34 (m, 1H), 2.27 (q, J = 12.2 Hz, 1H), 2.08 (bs, 1H). 13 C NMR (125 MHz, CDCl3): δ 178.4, 166.5, 146.8, 132.5, 130.2, 125.5, 125.3, 124.5 (C-F, q, 1 J CF = 278.0 Hz), 108.1, 61.5, 53.4 (CF, q, 2 J CF = 29.4 Hz), 52.2, 45.1, 37.1, 26.2, 15.1. IR: v 3302, 2950, 1709, 1616, 1498, 1453, 1298, 1235, 1161, 1093, 585 cm1; HRMS (EI) m/z: [M]+ Calcd. for C16H16F3N2O3I 468.0158; Found 468.0161.Compound D23 (Methyl 4'-iodo-1-methyl-2-oxo-6'-(trifluoromethyl)spiro[indoline-3) in the same manner as in Example 14, except that Compound 10 was used instead of Compound A1. ,2'-piperidine] -5-carboxylate) was prepared (yield: 75%). R f = 0.5 (EtOAc/Hexane = 1/2). Mp 255-256 °C; 1H NMR (500 MHz, CDCl 3 ): δ 8.06 (dd, J = 8.3 Hz, 1.7 Hz, 1H), 8.01 (d, J = 2.0 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H) , 4.99–4.93 (m, 1H), 4.50–4.44 (m, 1H), 3.90 (s, 3H), 3.19 (s, 3H), 2.71–2.67 (m, 1H), 2.51 (t, J = 13.0 Hz) , 1H), 2.37–2.34 (m, 1H), 2.27 (q, J = 12.2 Hz, 1H), 2.08 (bs, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 178.4, 166.5, 146.8, 132.5, 130.2, 125.5, 125.3, 124.5 (CF, q, 1 J CF = 278.0 Hz), 108.1, 61.5, 53.4 (CF, q, 2 J CF = 29.4 Hz), 52.2, 45.1, 37.1, 26.2, 15.1. IR : v 3302, 2950, 1709, 1616, 1498, 1453, 1298, 1235, 1161, 1093, 585 cm 1 ; HRMS (EI) m/z: [M] + Calcd. for C 16 H 16 F 3 N 2 O 3 I 468.0158; Found 468.0161.
[화합물 D23][Compound D23]
1.3. 추가적인 합성 결과 1.3. Additional synthesis results
상기 실시예 13에서 제조한 화합물 D4를 4 당량의 싸이오페놀, 4 당량의 NaH 및 0.24M의 디메틸포름아마이드와 혼합하여 80℃의 온도에서 2시간동안 반응하여 화합물 D24(1-Methyl-4'-(phenylthio)-6'-(trifluoromethyl)spiro[indoline-3,2'-piperidin]-2-one)를 제조하였다(수율 47%). R f = 0.5 (EtOAc/Hexane = 1/4). 1 H NMR (500 MHz, CDCl3): δ 7.42-7.41 (m, 2H), 7.38 (d, J = 7.0 Hz, 1H), 7.32-7.28 (m, 3H), 7.25-7.22 (m, 1H), 7.08 (t, J = 7.2 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 4.67-4.60 (m, 1H), 3.85-3.80 (m, 1H), 3.17 (s, 3H), 2.30 (dd, J = 14.5 Hz, 6.0 Hz, 1H), 2.25-2.21 (m, 2H), 2.10 (dd, J = 14.5 Hz, 7.0 Hz, 1H). 13 C NMR (125 MHz, CDCl3): δ 178.7, 142.9, 135.7, 131.7, 129.7, 129.2, 128.6 (C-F, q, 1 J CF = 302.2 Hz), 127.3, 123.9, 123.3, 108.4, 59.5, 50.0 (C-F, q, 2 J CF = 29.2 Hz), 40.2, 37.7, 29.3, 26.3. IR: v 3312, 2956, 2922, 2850, 1713, 1614, 1439, 1471, 1347, 1276, 1125, 751 cm1; HRMS (EI) m/z: [M]+ Calcd. For C20H19F3N2OS 392.1169; Found 392.1170.Compound D4 prepared in Example 13 was mixed with 4 equivalents of thiophenol, 4 equivalents of NaH and 0.24M dimethylformamide, reacted at 80 ° C. for 2 hours, and compound D24 (1-Methyl-4'-(phenylthio)-6'-(trifluoromethyl)spiro[indoline-3,2'-piperidin]-2-one) was prepared (yield: 47%). R f = 0.5 (EtOAc/Hexane = 1/4). 1 H NMR (500 MHz, CDCl 3 ): δ 7.42-7.41 (m, 2H), 7.38 (d, J = 7.0 Hz, 1H), 7.32-7.28 (m, 3H), 7.25-7.22 (m, 1H) , 7.08 (t, J = 7.2 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 4.67–4.60 (m, 1H), 3.85–3.80 (m, 1H), 3.17 (s, 3H), 2.30 (dd, J = 14.5 Hz, 6.0 Hz, 1H), 2.25–2.21 (m, 2H), 2.10 (dd, J = 14.5 Hz, 7.0 Hz, 1H). 13 C NMR (125 MHz, CDCl 3 ): δ 178.7, 142.9, 135.7, 131.7, 129.7, 129.2, 128.6 (CF, q, 1 J CF = 302.2 Hz), 127.3, 123.9, 123.3, 108.4, 59.5 , 50.0 ( CF, q, 2 J CF = 29.2 Hz), 40.2, 37.7, 29.3, 26.3. IR : v 3312, 2956, 2922, 2850, 1713, 1614, 1439, 1471, 1347, 1276, 1125, 751 cm 1 ; HRMS (EI) m/z: [M] + Calcd. For C 20 H 19 F 3 N 2 OS 392.1169; Found 392.1170.
[화합물 D24][Compound D24]
상기 실시예 1 내지 33에서는 다양한 기능기를 가진 스피로[인돌린-3,2'-피페리딘] 유도체를 제조하기 위해서 본 발명에 따른 합성 방법을 사용할 수 있다는 것을 확인할 수 있다. 특히, 종래에는 합성되지 않았던 6각고리인 피페리딘과 옥신돌의 스피로 화합물을 합성할 수 있으며, 단일 반응이 아닌 다단계 반응에서 합성 시약의 친핵체를 조절하여 C4' 위치에 치환되는 친핵체를 조절할 수 있다. 또한, 전이금속의 부재 하에서 단일 단계로 온화한 조건에서 합성할 수 있어 공정의 시간을 단축하고 저가화를 용이하게 달성할 수 있다. 나아가, 치환기를 다양하게 조절함으로써 다양한 스피로[인돌린-3,2'-피페리딘] 유도체를 제조할 수 있는 것을 확인할 수 있다. 더욱이, 전이금속을 사용하지 않고도 높은 수율로 합성할 수 있다. In Examples 1 to 33, it can be confirmed that the synthesis method according to the present invention can be used to prepare spiro[indoline-3,2'-piperidine] derivatives having various functional groups. In particular, it is possible to synthesize a spiro compound of piperidine and oxindole, which are hexagonal rings that have not been previously synthesized, and the nucleophile substituted at the C4' position can be controlled by controlling the nucleophile of the synthetic reagent in a multi-step reaction rather than a single reaction. there is. In addition, since it can be synthesized in a single step under mild conditions in the absence of a transition metal, the process time can be shortened and cost reduction can be easily achieved. Furthermore, it can be confirmed that various spiro[indoline-3,2'-piperidine] derivatives can be prepared by adjusting the substituent in various ways. Moreover, it can be synthesized in high yield without using a transition metal.
전술한 본원의 설명은 예시를 위한 것이며, 본원이 속하는 기술분야의 통상의 지식을 가진 자는 본원의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다. 예를 들어, 단일형으로 설명되어 있는 각 구성 요소는 분산되어 실시될 수도 있으며, 마찬가지로 분산된 것으로 설명되어 있는 구성 요소들도 결합된 형태로 실시될 수 있다.The above description of the present application is for illustrative purposes, and those skilled in the art will understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present application. Therefore, the embodiments described above should be understood as illustrative in all respects and not limiting. For example, each component described as a single type may be implemented in a distributed manner, and similarly, components described as distributed may be implemented in a combined form.
본원의 범위는 상기 상세한 설명보다는 후술하는 특허청구범위에 의하여 나타내어지며, 특허청구범위의 의미 및 범위 그리고 그 균등 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본원의 범위에 포함되는 것으로 해석되어야 한다.The scope of the present application is indicated by the following claims rather than the detailed description above, and all changes or modifications derived from the meaning and scope of the claims and equivalent concepts thereof should be construed as being included in the scope of the present application.
Claims (10)
[화학식 1]
상기 화학식 1에서,
R1은 H 또는 C1-6의 알킬이고,
R2 내지 R4는 각각 독립적으로 H, 할로겐, C1-6의 알킬, C1-6의 알콕시, -COOR5, 또는 -CN이고,
R5는 H 또는 C1-6의 알킬이고,
X는 F, Cl, Br, I, OH 또는 페닐싸이올(phenylthiol)이다.
A spiro[indoline-3,2'-piperidine] derivative represented by Formula 1 below:
[Formula 1]
In Formula 1,
R 1 is H or C 1-6 alkyl;
R 2 to R 4 are each independently H, halogen, C 1-6 alkyl, C 1-6 alkoxy, -COOR 5 , or -CN;
R 5 is H or C 1-6 alkyl;
X is F, Cl, Br, I, OH or phenylthiol.
상기 R1은 H 또는 메틸인 것인, 스피로[인돌린-3,2'-피페리딘] 유도체.
According to claim 1,
Wherein R 1 is H or methyl, a spiro [indoline-3,2'-piperidine] derivative.
상기 R2 내지 R4는 각각 독립적으로 H, 할로겐, 메틸, 메톡시기, -COOCH3, -CN 및 이들의 조합들로 이루어진 군에서 선택된 것을 포함하는 것인, 스피로[인돌린-3,2'-피페리딘] 유도체.
According to claim 1,
The R 2 to R 4 are each independently selected from the group consisting of H, halogen, methyl, methoxy group, -COOCH 3 , -CN, and combinations thereof, spiro [indoline-3,2' -piperidine] derivatives.
상기 스피로[인돌린-3,2'-피페리딘] 유도체는 하기 화합물 중 어느 하나를 선택하는 것인, 스피로[인돌린-3,2'-피페리딘] 유도체:
According to claim 1,
The spiro [indoline-3,2'-piperidine] derivative is selected from any one of the following compounds, a spiro [indoline-3,2'-piperidine] derivative:
상기 화학식 4 및 5로서 표시되는 화합물 및 합성 시약을 용매 하에서 반응시키는 단계;를 포함하며,
상기 합성 시약은 X를 포함하는, 하기 화학식 1로서 표시되는 스피로[인돌린-3,2'-피페리딘] 유도체의 제조 방법:
[화학식 1]
[화학식 2]
[화학식 3]
[화학식 4]
[화학식 5]
상기 화학식 1 내지 5에서,
R1은 H 또는 C1-6의 알킬이고,
R2 내지 R4는 각각 독립적으로 H, 할로겐, C1-6의 알킬, C1-6의 알콕시, -COOR5, 또는 -CN이고,
R5는 H 또는 C1-6의 알킬이고,
X는 F, Cl, Br, I, OH 또는 페닐싸이올(phenylthiol)이다.
Preparing a compound represented by Formula 4 and a compound represented by Formula 5 by reacting a compound represented by Formula 2, a compound represented by Formula 3, and a base in a solvent; and
Including; reacting the compounds represented by Formulas 4 and 5 and synthetic reagents in a solvent,
Method for producing a spiro[indoline-3,2'-piperidine] derivative represented by Formula 1 below, wherein the synthetic reagent includes X:
[Formula 1]
[Formula 2]
[Formula 3]
[Formula 4]
[Formula 5]
In Formulas 1 to 5,
R 1 is H or C 1-6 alkyl;
R 2 to R 4 are each independently H, halogen, C 1-6 alkyl, C 1-6 alkoxy, -COOR 5 , or -CN;
R 5 is H or C 1-6 alkyl;
X is F, Cl, Br, I, OH or phenylthiol.
상기 반응은 화학식 2로서 표시되는 화합물과 상기 화학식 3으로서 표시되는 화합물이 상기 염기와 극성 반전 알릴화 반응으로 상기 화학식 4 로서 표시되는 화합물 및 상기 화학식 5로서 표시되는 화합물을 형성하는 것인, 스피로[인돌린-3,2'-피페리딘] 유도체의 제조 방법.
According to claim 5,
The reaction is a spiro[ A method for preparing an indoline-3,2'-piperidine] derivative.
상기 반응은 상기 화학식 4 로서 표시되는 화합물 및 상기 화학식 5로서 표시되는 화합물과 상기 합성 시약이 아자-프린스 고리화 반응을 수행하는 것인, 스피로[인돌린-3,2'-피페리딘] 유도체의 제조 방법.
According to claim 5,
The reaction is a spiro[indoline-3,2'-piperidine] derivative wherein the compound represented by Formula 4 and the compound represented by Formula 5 and the synthetic reagent undergo an aza-prince cyclization reaction. manufacturing method.
상기 합성 시약은 트리메틸실릴브로마이드(Trimethylsilyl bromide), 트리메틸실릴클로라이드(Trimethylsilyl chloride), 트리메틸실릴플루오라이드(Trimethylsilyl fluoride), 트리메틸실릴아이오디드(Trimethylsilyl iodide), 트리메틸실릴트리플레이트(Trimethylsilyl triflate), 트리에틸실릴트리플레이트(Triethylsilyl triflate), BF3·OEt2, TiCl4, FeCl3, Cu(OTf)2, InCl3 및 이들의 조합들로 이루어진 군에서 선택된 것을 포함하는 것인, 스피로[인돌린-3,2'-피페리딘] 유도체의 제조 방법.
According to claim 5,
The synthesis reagent is trimethylsilyl bromide, trimethylsilyl chloride, trimethylsilyl fluoride, trimethylsilyl iodide, trimethylsilyl triflate, triethylsilyl Triflate (Triethylsilyl triflate), BF 3 OEt 2 , TiCl 4 , FeCl 3 , Cu(OTf) 2 , InCl 3 and combinations thereof, including those selected from the group consisting of spiro [indoline-3, Method for preparing a 2'-piperidine] derivative.
상기 용매는 디클로로에테인, 디클로로메테인, 아세토니트릴, 클로로포름, 테트라하이드로퓨란, 톨루엔 및 이들의 조합들로 이루어진 군에서 선택된 것을 포함하는 것인, 스피로[인돌린-3,2'-피페리딘] 유도체의 제조 방법.
According to claim 5,
The solvent includes dichloroethane, dichloromethane, acetonitrile, chloroform, tetrahydrofuran, toluene, and combinations thereof, spiro [indoline-3,2'-piperidine] Methods for preparing derivatives.
상기 염기는 1,8-디아자바이사이클로[5,4,0]언덱-7-엔 (1,8-Diazabicyclo[5.4.0]undec-7-ene, DBU), 트리에틸아민(triethylamine, TEA), 디이소프로필에틸아민(N,N-diisopropylethylamine, DIPEA), K2CO3, (CH3)3COK, Cs2CO3 및 이들의 조합들로 이루어진 군에서 선택된 것을 포함하는 것인, 스피로[인돌린-3,2'-피페리딘] 유도체의 제조 방법.
According to claim 5,
The base is 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), triethylamine (TEA) , diisopropylethylamine (N,N-diisopropylethylamine, DIPEA), K 2 CO 3 , (CH 3 ) 3 COK, Cs 2 CO 3 and those containing those selected from the group consisting of combinations thereof, spiro [ A method for preparing an indoline-3,2'-piperidine] derivative.
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