CN106008477B - 3-(2-芳基-1h-吲哚-3-基)-4-羟基呋喃-2(5h)-酮及其合成方法 - Google Patents
3-(2-芳基-1h-吲哚-3-基)-4-羟基呋喃-2(5h)-酮及其合成方法 Download PDFInfo
- Publication number
- CN106008477B CN106008477B CN201610389382.0A CN201610389382A CN106008477B CN 106008477 B CN106008477 B CN 106008477B CN 201610389382 A CN201610389382 A CN 201610389382A CN 106008477 B CN106008477 B CN 106008477B
- Authority
- CN
- China
- Prior art keywords
- acid
- indol
- aryl
- catalyst
- arh
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000010189 synthetic method Methods 0.000 title claims description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 29
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 27
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 18
- 239000003054 catalyst Substances 0.000 claims abstract description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 12
- PGRHXDWITVMQBC-UHFFFAOYSA-N dehydroacetic acid Chemical class CC(=O)C1C(=O)OC(C)=CC1=O PGRHXDWITVMQBC-UHFFFAOYSA-N 0.000 claims abstract description 11
- PEQJBOMPGWYIRO-UHFFFAOYSA-N n-ethyl-3,4-dimethoxyaniline Chemical class CCNC1=CC=C(OC)C(OC)=C1 PEQJBOMPGWYIRO-UHFFFAOYSA-N 0.000 claims abstract description 11
- 150000001448 anilines Chemical class 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 230000005855 radiation Effects 0.000 claims abstract description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 26
- VIHAEDVKXSOUAT-UHFFFAOYSA-N but-2-en-4-olide Chemical compound O=C1OCC=C1 VIHAEDVKXSOUAT-UHFFFAOYSA-N 0.000 claims description 21
- 230000015572 biosynthetic process Effects 0.000 claims description 10
- 238000003786 synthesis reaction Methods 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-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
- ZXPNUUFATNGXAW-UHFFFAOYSA-N benzene;oxaldehyde Chemical class O=CC=O.C1=CC=CC=C1 ZXPNUUFATNGXAW-UHFFFAOYSA-N 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 238000010490 three component reaction Methods 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 9
- 238000006452 multicomponent reaction Methods 0.000 abstract description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 abstract description 3
- 150000007529 inorganic bases Chemical class 0.000 abstract description 3
- 150000007522 mineralic acids Chemical class 0.000 abstract description 3
- 150000002825 nitriles Chemical class 0.000 abstract description 3
- 150000007524 organic acids Chemical class 0.000 abstract description 3
- 230000035484 reaction time Effects 0.000 abstract description 3
- 238000001308 synthesis method Methods 0.000 abstract description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 abstract 1
- 235000019606 astringent taste Nutrition 0.000 abstract 1
- 150000003935 benzaldehydes Chemical class 0.000 abstract 1
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 abstract 1
- 238000009835 boiling Methods 0.000 abstract 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 abstract 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 abstract 1
- 238000005580 one pot reaction Methods 0.000 abstract 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 42
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 18
- -1 furans heterocyclic compounds Chemical class 0.000 description 13
- 150000002240 furans Chemical class 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 9
- 239000003814 drug Substances 0.000 description 8
- 235000019441 ethanol Nutrition 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- OJUGVDODNPJEEC-UHFFFAOYSA-N phenylglyoxal Chemical compound O=CC(=O)C1=CC=CC=C1 OJUGVDODNPJEEC-UHFFFAOYSA-N 0.000 description 6
- WDFQBORIUYODSI-UHFFFAOYSA-N 4-bromoaniline Chemical compound NC1=CC=C(Br)C=C1 WDFQBORIUYODSI-UHFFFAOYSA-N 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 235000002566 Capsicum Nutrition 0.000 description 4
- 239000006002 Pepper Substances 0.000 description 4
- 241000722363 Piper Species 0.000 description 4
- 235000016761 Piper aduncum Nutrition 0.000 description 4
- 235000017804 Piper guineense Nutrition 0.000 description 4
- 235000008184 Piper nigrum Nutrition 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- 150000002475 indoles Chemical class 0.000 description 3
- 125000006237 oxymethylenoxy group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 3
- 239000000575 pesticide Substances 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 2
- WRDWWAVNELMWAM-UHFFFAOYSA-N 4-tert-butylaniline Chemical compound CC(C)(C)C1=CC=C(N)C=C1 WRDWWAVNELMWAM-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
- UCHDWCPVSPXUMX-TZIWLTJVSA-N Montelukast Chemical compound CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC(O)=O)CC1 UCHDWCPVSPXUMX-TZIWLTJVSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 150000001555 benzenes Chemical class 0.000 description 2
- 239000000686 essence Substances 0.000 description 2
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 229960005127 montelukast Drugs 0.000 description 2
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 description 2
- 238000012216 screening Methods 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
- WNPVZANXRCPJPW-UHFFFAOYSA-N 5-[isocyano-(4-methylphenyl)sulfonylmethyl]-1,2,3-trimethoxybenzene Chemical compound COC1=C(OC)C(OC)=CC(C([N+]#[C-])S(=O)(=O)C=2C=CC(C)=CC=2)=C1 WNPVZANXRCPJPW-UHFFFAOYSA-N 0.000 description 1
- JLUQTCXCAFSSLD-NXEZZACHSA-N Anemonin Chemical compound C1=CC(=O)O[C@]11[C@@]2(C=CC(=O)O2)CC1 JLUQTCXCAFSSLD-NXEZZACHSA-N 0.000 description 1
- JLUQTCXCAFSSLD-UHFFFAOYSA-N Anemonin Natural products C1=CC(=O)OC11C2(C=CC(=O)O2)CC1 JLUQTCXCAFSSLD-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- JBNBNDGMKZGCHD-UHFFFAOYSA-N C1=CC=C(C=C1)C(=O)CC(=O)Br Chemical compound C1=CC=C(C=C1)C(=O)CC(=O)Br JBNBNDGMKZGCHD-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 241000601164 Clematis orientalis Species 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- 102000030595 Glucokinase Human genes 0.000 description 1
- 108010021582 Glucokinase Proteins 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 239000008896 Opium Substances 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 102100038824 Peroxisome proliferator-activated receptor delta Human genes 0.000 description 1
- JPRXYLQNJJVCMZ-UHFFFAOYSA-N Rizatriptan benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1.C1=C2C(CC[NH+](C)C)=CNC2=CC=C1CN1C=NC=N1 JPRXYLQNJJVCMZ-UHFFFAOYSA-N 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 230000000895 acaricidal effect Effects 0.000 description 1
- 239000000642 acaricide Substances 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000001857 anti-mycotic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000002543 antimycotic Substances 0.000 description 1
- 239000003972 antineoplastic antibiotic Substances 0.000 description 1
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000029771 childhood onset asthma Diseases 0.000 description 1
- 229940126678 chinese medicines Drugs 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 230000009514 concussion Effects 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 229940103177 maxalt Drugs 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229960001027 opium Drugs 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- YCOFRPYSZKIPBQ-UHFFFAOYSA-N penicillic acid Natural products COC1=CC(=O)OC1(O)C(C)=C YCOFRPYSZKIPBQ-UHFFFAOYSA-N 0.000 description 1
- VOUGEZYPVGAPBB-UHFFFAOYSA-N penicillin acid Natural products OC(=O)C=C(OC)C(=O)C(C)=C VOUGEZYPVGAPBB-UHFFFAOYSA-N 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 108091008765 peroxisome proliferator-activated receptors β/δ Proteins 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 229960000371 rofecoxib Drugs 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- DTDSAWVUFPGDMX-UHFFFAOYSA-N spirodiclofen Chemical compound CCC(C)(C)C(=O)OC1=C(C=2C(=CC(Cl)=CC=2)Cl)C(=O)OC11CCCCC1 DTDSAWVUFPGDMX-UHFFFAOYSA-N 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种3‑(2‑芳基‑1H‑吲哚‑3‑基)‑4‑羟基呋喃‑2(5H)‑酮的合成方法，该合成方法是以取代苯甲酰甲醛、取代苯胺和季酮酸为原料，以醇、醚、腈、水、二甲亚砜、N,N‑二甲基甲酰胺、醋酸或芳香烃化合物为溶剂，在不使用催化剂，或以无机碱、无机酸、有机酸或有机小分子化合物为催化剂的情况下，在微波辐射下利用多组分反应，将这三种原料通过“一锅煮”的方法合成了一种同时具有呋喃‑2(5H)‑酮和吲哚两种骨架的新型化合物。本发明的合成方法具有反应时间较短，条件较为简单，高产率，高原子经济性，收敛性以及易操作等优点。
Description
技术领域
本发明属于有机化合成领域，具体而言，涉及一种3-(2-芳基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮及其合成方法。
背景技术
呋喃-2(5H)-酮是一种重要的呋喃类杂环化合物，它广泛存在自然界中，维生素C(结构式1)和青霉酸(结构式2)是人们最为熟悉的呋喃-2(5H)-酮衍生物。4,5-二甲基-3-羟基呋喃-2(5H)-酮(结构式3)是一种具有香味的物质(R.Kazlauskas,P.T.Murphy,R.J.Quinn,R.J.Wells,Tetrahedron Lett.,1977,18,37)。某些重要中药的有效成分，也含有呋喃-2(5H)-酮结构的化合物，例如：威灵仙中的白头翁素(结构式4)等(吕丹，海峡药学，1999,11,7)。
呋喃-2(5H)-酮结构的化合物具有广泛的生物和药理学活性，例如：抗真菌、抗炎、抗病毒、抗癌等等((a)G.Grossmann,M.Poncioni,M.Bornand,B.Jolivet,M.Neuburger,U.Sequin,Tetrahedron,2003,59,3237.)。近几年又发现该类骨架的化合物具有抑制细菌群体效应的活性((a)M.Hentzer,K.Riedel,T.B.Rasmussen,A.Heydorn,J.B.Andersen,M.R.Parsen,S.A.Rice,L.Eberl,S.Molin,N.Hoiby,S.Kjelleberg,M.Givskov,Microbiology,2002,148,87；(b)D.Ren,R.Zuo,T.K.Wood,Applied Microbiology andBiotechnology,2005,66,689.)。一些具有呋喃-2(5H)-酮结构的化合物研究应用于药物和农药中，例如：新型非甾体抗炎药物罗昔布(rofecoxib,MK 966)(结构式5)(嵇汝运，国外医药合成药，生化药，制剂分册，1999,20,258.)和农药杀螨剂螺螨酯(结构式6)(R.Fischer,T.Bretschneider,B.W.Krueger,DE,4216814,1993.01.21.)及螺虫酯(结构式7)(U.Wachendorff-Neumann,WO,20000042850,2000.07.27.)都具有呋喃-2(5H)-酮骨架。
吲哚类化合物是自然界中分布最广的杂环化合物，作为医药、农药、染料和其它精细化工产品的中间体，其应用越来越广。首先，吲哚环在许多药物中是一个重要的骨架，比如治疗成年人和儿童哮喘的新药顺尔宁(Singulair)，以及治疗偏头痛药物(Maxalt)；同样，针对结肠、乳腺癌细胞具有高选择性的抗肿瘤活性的吲哚-醌醇化合物，其结构式为(A.J.McCarroll,T.D.Bradshaw,A.D.Westwell,C.S.Matthews,M.F.G.Stevens.J.Med.Chem.,2007,50,1707)；吲哚衍生物可作为神经保护药物，高效阿片受体兴奋剂，治疗骨质疏松症药物PPAR-c，治疗周围神经病变以及神经退化疾病的药物，葡萄糖激酶活化剂，细胞毒性抗生素CC-1065和它的前体药物，以及治疗心血管疾病催化剂PPAR-delta(G.Bratulescu,Tetrahedron Lett.,2008,49,984)。
多组分反应就是一种符合环境友好型的合成方法学，多组分反应是将三个或者三个以上的原料通过“一锅煮”的方法合成包含所有组分主要结构片段的新化合物的过程。多组分具有高产率、高原子经济性、收敛性以及易操作等优点。通过多组分反应可以利用一些简单易得的原料，方便、高效地构建具有结构多样性和复杂性的化合物，该方法已经广泛应用于各种杂环化合物的合成。
发明内容
基于呋喃-2(5H)-酮骨架和吲哚骨架所具有的重要的生物和药理学活性，本发明的目的是利用多组分反应的合成方法，一步合成一种同时具有呋喃-2(5H)-酮和吲哚两种骨架的新型化合物，该种新型化合物具有潜在应用价值。
为实现上述技术目的，达到上述技术效果，本发明通过以下技术方案实现：
一种3-(2-芳基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮，其结构如下所示：
其中，R1为H、4-CH3或4-Br中的任意一种；R2为5-Br、5-CH3、5-(CH3)3C、5,6-OCH2O或4-Cl中的任意一种。
一种3-(2-芳基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮的合成方法，是以取代苯甲酰甲醛(式I)、取代苯胺(式II)和季酮酸(式III)为原料，以醇、醚、腈、水、二甲亚砜、N,N-二甲基甲酰胺、醋酸或芳香烃化合物为溶剂，在不使用催化剂，或以无机碱、无机酸、有机酸或有机小分子化合物为催化剂的情况下，在微波辐射下经过三组分反应，一步合成得到目标化合物，一步合成得到目标化合物，即3-(2-芳基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮衍生物(式IV)：
其反应式如下：
进一步的，所述溶剂为甲醇、乙醇、1,4-二氧六环、四氢呋喃、乙腈、N,N-二甲基甲酰胺、二甲亚砜、醋酸、甲苯、水或水与乙醇的混合溶剂中的任意一种。
进一步的，所述催化剂为碳酸钠、碳酸钾、盐酸、硫酸、醋酸、三氟乙酸、对甲苯磺酸或L-脯氨酸中的任意一种。
进一步的，所述取代苯甲酰甲醛、所述取代苯胺、所述季酮酸和所述催化剂的摩尔比为1:1:1:0.1～1:1:1:0.3。
进一步的，该反应的反应时间为20～50分钟。
进一步的，该反应的反应温度为60～100℃。
经过多次反应条件的筛选，并考虑到反应的效果和绿色化学的原则，作为优选，确定以水和乙醇组成(体积比为1:1)的混合溶剂作为溶剂，以三氟乙酸作为催化剂，将取代苯甲酰甲醛、取代苯胺、季酮酸和三氟乙酸按照1:1:1:0.2的摩尔比，在反应温度为90℃的条件下反应40分钟，得到的目标产物的收率最高。
本发明的有益效果是：
本发明的合成方法利用多组分反应，将三种原料通过“一锅煮”的方法合成了一种同时具有呋喃-2(5H)-酮和吲哚两种骨架的新型化合物，该种新型化合物具有的重要的生物和药理学活性，以及具有潜在应用价值。与现有技术相比，本发明的合成方法具有反应时间较短，条件较为简单，高产率，高原子经济性，收敛性以及易操作等优点。
上述说明仅是本发明技术方案的概述，为了能够更清楚了解本发明的技术手段，并可依照说明书的内容予以实施，以下以本发明的较佳实施例详细说明。本发明的具体实施方式由以下实施例详细给出。
具体实施方式
下面将结合实施例，来详细说明本发明。
一种3-(2-芳基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮，其结构如下所示：
其中，R1为H、4-CH3或4-Br中的任意一种；R2为5-Br、5-CH3、5-(CH3)3C、5,6-OCH2O或4-Cl中的任意一种。
一种3-(2-芳基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮的合成方法，是以取代苯甲酰甲醛(式I)、取代苯胺(式II)和季酮酸(式III)为原料，以醇、醚、腈、水、二甲亚砜、N,N-二甲基甲酰胺、醋酸或芳香烃化合物为溶剂，在不使用催化剂，或以无机碱、无机酸、有机酸或有机小分子化合物为催化剂的情况下，在微波辐射下经过三组分反应，一步合成得到目标化合物，一步合成得到目标化合物，即3-(2-芳基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮衍生物(式IV)：
其反应式如下：
本发明的合成方法，是由取代苯甲酰甲醛、取代苯胺、季酮酸、催化剂和适当溶剂所组成的反应体系在微波辐射下进行的。其中，所述取代苯甲酰甲醛、所述取代苯胺、所述季酮酸和所述催化剂的摩尔比为1:1:1:0.1～1:1:1:0.3。
本发明的合成方法中所使用的溶剂为甲醇、乙醇、1,4-二氧六环、四氢呋喃、乙腈、N,N-二甲基甲酰胺、二甲亚砜、醋酸、甲苯、水或水与乙醇的混合溶剂中的任意一种。
本发明的合成方法中所使用的催化剂为碳酸钠、碳酸钾、盐酸、硫酸、醋酸、三氟乙酸、对甲苯磺酸或L-脯氨酸中的任意一种。
本发明的合成方法的反应时间为20～50分钟。
本发明的合成方法的反应温度为60～100℃。
经过多次反应条件的筛选，并考虑到反应的效果和绿色化学的原则，作为优选，确定以水和乙醇组成(体积比为1:1)的混合溶剂作为溶剂，以三氟乙酸作为催化剂，将取代苯甲酰甲醛、取代苯胺、季酮酸和三氟乙酸按照1:1:1:0.2的摩尔比，在反应温度为90℃的条件下反应40分钟，得到的目标产物的收率最高。
下面由以下实施例对该种3-(2-芳基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮的合成方法进行详细举例和说明：
实施例1
将苯甲酰甲醛(1mmol)、对溴苯胺(1mmol)、季酮酸(1mmol)加入微波反应管，加入4mL EtOH/H2O(体积比为1:1)，稍加震荡使底物混合均匀，滴加(0.2mmol)三氟乙酸，微波反应器于90℃反应40min，用TLC监测反应进程，待反应结束后通过柱层析得到产物，为3-(5-溴-2-苯基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮(化合物IVa)，收率为65％。化合物的结构通过核磁共振谱确定。熔点为280～282℃。1H NMR(400MHz,DMSO-d6)δ(ppm):12.19(s,1H,OH),11.76(s,1H,NH),7.67(d,J＝7.6Hz,2H,ArH),7.45(s,1H,ArH),7.44(t,J＝7.6Hz,2H,ArH),7.40-7.32(m,2H,ArH),7.25(d,J＝8.4Hz,1H,ArH),4.87(s,2H,CH2)。
实施例2
按照实施例1的方法，将对溴苯胺换成对甲苯胺，加入(0.2mmol)三氟乙酸，微波反应器于90℃反应40min，用TLC监测反应进程，待反应结束后通过柱层析得到产物，为3-(5-甲基-2-苯基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮(化合物IVb)，收率为57％，熔点为276～277℃。1H NMR(400MHz,DMSO-d6)δ(ppm):11.95(s,1H,OH),11.39(s,1H,NH),7.65(d,J＝7.6Hz,2H,ArH),7.42(t,J＝7.6Hz,2H,ArH),7.30(t,J＝8.4Hz,2H,ArH),7.09(s,1H,ArH),6.96(d,J＝8.4Hz,1H,ArH),4.85(s,2H,CH2),2.37(s,3H,CH3)。
实施例3
按照实施例1的方法，将对溴苯胺换成对叔丁基苯胺，加入(0.2mmol)三氟乙酸，微波反应器于90℃反应40min，用TLC监测反应进程，待反应结束后通过柱层析得到产物，为3-(5-叔丁基-2-苯基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮(化合物IVc)，收率为71％，熔点为250～251℃。1H NMR(400MHz,DMSO-d6)δ(ppm):11.53(s,1H,OH),11.38(s,1H,NH),7.65(d,J＝7.2Hz,2H,ArH),7.42(t,J＝7.6Hz,2H,ArH),7.35(d,J＝8.4Hz,1H,ArH),7.30(t,J＝7.2Hz,2H,ArH),7.24(d,J＝8.8Hz,1H,ArH),4.88(s,2H,CH2),1.33(s,9H,(CH3)3C)。
实施例4
按照实施例1的方法，将对溴苯胺换成3,4-亚甲二氧基苯胺(胡椒胺)，加入(0.2mmol)三氟乙酸，微波反应器于90℃反应40min，用TLC监测反应进程，待反应结束后通过柱层析得到产物，为3-(5,6-亚甲二氧基-2-苯基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮(化合物IVd)，收率为72％，熔点为244～246℃。1H NMR(400MHz,DMSO-d6)δ(ppm):12.09(s,1H,OH),11.38(s,1H,NH),7.62(d,J＝7.6Hz,2H,ArH),7.40(t,J＝7.6Hz,2H,ArH),7.26(t,J＝7.2Hz,1H,ArH),6.94(s,1H,ArH),6.77(s,1H,ArH),5.96(s,2H,OCH2O),4.86(s,2H,CH2)。
实施例5
按照实施例1的方法，将苯甲酰甲醛换成对甲基苯甲酰甲醛，加入(0.2mmol)三氟乙酸，微波反应器于90℃反应40min，用TLC监测反应进程，待反应结束后通过柱层析得到产物，为3-(5-溴-2-对甲苯基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮(化合物IVe)，收率为64％，熔点为266～267℃。1H NMR(400MHz,DMSO-d6)δ(ppm):12.17(s,1H,OH),11.70(s,1H,NH),7.56(d,J＝8.0Hz,2H,ArH),7.47(s,1H,ArH),7.37(d,J＝8.4Hz,1H,ArH),7.26-7.22(m,3H,ArH),4.86(s,2H,CH2),2.34(s,3H,CH3)。
实施例6
按照实施例4的方法，将对溴苯胺换成3,4-亚甲二氧基苯胺(胡椒胺)，加入(0.2mmol)三氟乙酸，微波反应器于90℃反应40min，用TLC监测反应进程，待反应结束后通过柱层析得到产物，为3-(5,6-亚甲二氧基-2-对甲苯基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮(化合物IVf)，收率为78％，熔点为280～281℃。1H NMR(400MHz,DMSO-d6)δ(ppm):12.05(s,1H,OH),11.30(s,1H,NH),7.49(d,J＝7.6Hz,2H,ArH),7.20(d,J＝8.0Hz,2H,ArH),6.92(s,1H,ArH),6.74(s,1H,ArH),5.95(s,2H,OCH2O),4.84(s,2H,CH2),2.32(s,3H,CH3)。
实施例7
按照实施例4的方法，将3,4-亚甲二氧基苯胺(胡椒胺)换成对叔丁基苯胺，加入(0.2mmol)三氟乙酸，微波反应器于90℃反应40min，用TLC监测反应进程，待反应结束后通过柱层析得到产物，为3-(5-叔丁基-2-对甲苯基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮(化合物IVg)，收率为69％，熔点为268～270℃。1H NMR(400MHz,DMSO-d6)δ(ppm):11.82(s,1H,OH),11.32(s,1H,NH),7.53(d,J＝8.0Hz,2H,ArH),7.34(d,J＝8.4Hz,1H,ArH),7.26-7.21(m,4H,ArH),4.86(s,2H,CH2),2.33(s,3H,CH3),1.33(s,9H,(CH3)3C)。
实施例8
按照实施例4的方法，将苯甲酰甲醛换成对溴苯甲酰甲醛，加入(0.2mmol)三氟乙酸，微波反应器于90℃反应40min，用TLC监测反应进程，待反应结束后通过柱层析得到产物，为3-(5,6-亚甲二氧基-2-对溴苯基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮(化合物IVh)，收率为73％，熔点为278～279℃。1H NMR(400MHz,DMSO-d6)δ(ppm):12.12(s,1H,OH),11.44(s,1H,NH),7.58(d,J＝8.8Hz,2H,ArH),7.53(d,J＝8.8Hz,2H,ArH),6.92(s,1H,ArH),6.77(s,1H,ArH),5.96(s,2H,OCH2O),4.84(s,2H,CH2)。
实施例9
按照实施例8的方法，将3,4-亚甲二氧基苯胺(胡椒胺)换成对氯苯胺，加入(0.2mmol)三氟乙酸，微波反应器于90℃反应40min，用TLC监测反应进程，待反应结束后通过柱层析得到产物，为3-(5-氯-2-对溴苯基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮(化合物IVi)，收率为61％，熔点为289～290℃。1H NMR(400MHz,DMSO-d6)δ(ppm):12.25(s,1H,OH),11.82(s,1H,NH),7.66-7.59(m,4H,ArH),7.43(d,J＝8.4Hz,1H,ArH),7.38(s,1H,ArH),7.16(d,J＝8.8Hz,1H,ArH),4.86(s,2H,CH2)。
上述实施例只是为了说明本发明的技术构思及特点，其目的是在于让本领域内的普通技术人员能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡是根据本发明内容的实质所作出的等效的变化或修饰，都应涵盖在本发明的保护范围内。
Claims (2)
1.一种3-(2-芳基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮的合成方法，所述的3-(2-芳基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮的结构如下所示：
其中，R1为4-CH3或4-Br中的任意一种；R2为5-CH3、5-(CH3)3C、5,6-OCH2O或4-Cl中的任意一种；
其特征在于，所述的3-(2-芳基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮的合成方法如下：
是以式I所示的取代苯甲酰甲醛、式II所示的取代苯胺和式III所示的季酮酸为原料，以甲醇、1,4-二氧六环、四氢呋喃、乙腈、N,N-二甲基甲酰胺、二甲亚砜、醋酸或甲苯中的任意一种为溶剂，在不使用催化剂，或以碳酸钠、碳酸钾、盐酸、硫酸、三氟乙酸或L-脯氨酸中的任意一种为催化剂的情况下，在90℃微波辐射下经过20～50分钟三组分反应，一步合成得到式IV所示的目标化合物，即3-(2-芳基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮衍生物：
2.根据权利要求1所述的3-(2-芳基-1H-吲哚-3-基)-4-羟基呋喃-2(5H)-酮的合成方法，其特征在于：所述取代苯甲酰甲醛、所述取代苯胺、所述季酮酸和所述催化剂的摩尔比为1:1:1:0.1～1:1:1:0.3。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610389382.0A CN106008477B (zh) | 2016-06-02 | 2016-06-02 | 3-(2-芳基-1h-吲哚-3-基)-4-羟基呋喃-2(5h)-酮及其合成方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610389382.0A CN106008477B (zh) | 2016-06-02 | 2016-06-02 | 3-(2-芳基-1h-吲哚-3-基)-4-羟基呋喃-2(5h)-酮及其合成方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106008477A CN106008477A (zh) | 2016-10-12 |
| CN106008477B true CN106008477B (zh) | 2019-02-26 |
Family
ID=57090487
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610389382.0A Active CN106008477B (zh) | 2016-06-02 | 2016-06-02 | 3-(2-芳基-1h-吲哚-3-基)-4-羟基呋喃-2(5h)-酮及其合成方法 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106008477B (zh) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1660790A (zh) * | 2004-12-21 | 2005-08-31 | 浙江大学 | 2，6－二氰基苯胺衍生物的微波合成方法 |
| CN101654425A (zh) * | 2009-09-11 | 2010-02-24 | 浙江工业大学 | L-脯氨酸三氟甲磺酸铵盐及其应用 |
| WO2012025155A1 (en) * | 2010-08-26 | 2012-03-01 | Novartis Ag | Hydroxamate-based inhibitors of deacetylases |
-
2016
- 2016-06-02 CN CN201610389382.0A patent/CN106008477B/zh active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1660790A (zh) * | 2004-12-21 | 2005-08-31 | 浙江大学 | 2，6－二氰基苯胺衍生物的微波合成方法 |
| CN101654425A (zh) * | 2009-09-11 | 2010-02-24 | 浙江工业大学 | L-脯氨酸三氟甲磺酸铵盐及其应用 |
| WO2012025155A1 (en) * | 2010-08-26 | 2012-03-01 | Novartis Ag | Hydroxamate-based inhibitors of deacetylases |
Non-Patent Citations (5)
| Title |
|---|
| "Microwave-assisted synthesis of novel 2,3-disubstituted imidazo[1,2-a]pyridines via one-pot three component reactions";Shaik Karamthulla，等;《RSC Adv.》;20150210;第5卷;第19724-19733页 * |
| "Three-component domino [3+2] heterocyclization leading to pyran-3-yl-substituted fused pyrroles";Shuang-Shuang Wang，等;《Res Chem Intermed》;20130924;第41卷;第2879-2889页 * |
| "Three-Component Domino Reactions for Regioselective Formation of Bis-indole Derivatives";Li-Ping Fu，等;《ACS Comb. Sci.》;20130122;第15卷;第135-140页 * |
| "Three-Component Reaction of a 2-Aminoazine, a 2-Oxoaldehyde, and a Cyclic 1,3-Dicarbonyl Compound for the Synthesis of Imidazo[1,2-a]azine Derivatives";Vsevolod A. Peshkov，等;《ACS Comb. Sci.》;20140829;第16卷;第535-542页 * |
| Shaik Karamthulla，等."Microwave-assisted synthesis of novel 2,3-disubstituted imidazo[1,2-a]pyridines via one-pot three component reactions".《RSC Adv.》.2015,第5卷第19724-19733页. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106008477A (zh) | 2016-10-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Redkin et al. | Synthesis and molecular structure of spirocyclic 2-oxindole derivatives of 2-amino-4H-pyran condensed with the pyrazolic nucleus | |
| US20110065681A1 (en) | Amide compounds, compositions and uses thereof | |
| Lotfy et al. | Regio-and stereoselective synthesis of new spirooxindoles via 1, 3-dipolar cycloaddition reaction: Anticancer and molecular docking studies | |
| JP2007514746A (ja) | Ｃｘｃ−ケモカインレセプターリガンドおよびｃｃ−ケモカインレセプターリガンドとしてのチアジアゾール | |
| Manasa et al. | Synthesis, antioxidant and anticancer activity of quinazoline derivatives | |
| Rouhani et al. | Perlite–SO 3 H nanoparticles: very efficient and reusable catalyst for three-component synthesis of N-cyclohexyl-3-aryl-quinoxaline-2-amine derivatives under ultrasound irradiation | |
| Lácová et al. | A facile route to phenyl, phenylsulfanyl and phenylselanyl substituted pyrano [3, 2-c] chromenes | |
| Panda et al. | “On water” synthesis of spiro-indoles via Schiff bases | |
| CA2655202A1 (en) | Glucocorticoid receptor modulator and methods of use | |
| Rizk et al. | Ultrasonic and Grinding Aptitudes of One‐Pot Synthesis of 5‐(4‐Chlorophenyl)‐7‐(3, 4‐Dimethyl Phenyl)‐2‐oxo‐2H‐Pyrano [2, 3‐b] Pyridine Derivatives as Antibacterial Agents | |
| Kusurkar et al. | Use of the Pictet–Spengler reaction for the synthesis of 1, 4-disubstituted-1, 2, 3, 4-tetrahydro-β-carbolines and 1, 4-disubstituted-β-carbolines: formation of γ-carbolines | |
| Nasri et al. | Synthesis of new functionalized thiazolo pyridine-fused and thiazolo pyridopyrimidine-fused spirooxindoles via one-pot reactions | |
| Ashok et al. | Facile ionic liquid-mediated, microwave assisted green synthesis, and antioxidant studies of novel indolin-2-one annulated spirochromanone conjugates | |
| Deshmukh et al. | Synthesis of quinazolinones derivatives an antiproliferative agent against human lung carcinoma cells | |
| Refat et al. | Synthesis and antitumor evaluation of some new biscarboxamidocoumarin and chromene derivatives | |
| CN106008477B (zh) | 3-(2-芳基-1h-吲哚-3-基)-4-羟基呋喃-2(5h)-酮及其合成方法 | |
| Behbehani et al. | Green protocol for the novel synthesis of thiochromeno [4, 3-b] pyridine and chromeno [4, 3-b] pyridine derivatives utilizing a high-pressure system | |
| Bhosale et al. | One-pot three-component condensation for the synthesis of 1, 4-dihydropyrano [2, 3-c] pyrazoles using cesium fluoride as an efficient catalyst | |
| Sun et al. | Access to indenofurans and indenopyridines via annulation of heterocyclic ketene aminals, o-phthalaldehyde and cyclic 1, 3-diketones | |
| Kanishcheva et al. | Thermolysis of 3-Azido-N-Phenylthieno-[2, 3-b] pyridine-2-Carboxamides | |
| Balalaie et al. | Synthesis of fully functionalized 3-bromoazaspiro [4.5] trienones through Ugi four-component reaction (Ugi-4CR) followed by ipso-bromocyclization | |
| Hamza et al. | Synthesis and in vitro anticancer evaluation of novel pyridine derivatives bearing tetrahydronaphthalene scaffold | |
| Sanghavi et al. | An efficient protocol for the synthesis of substituted 5‐amino pyrazole bearing benzo [d] imidazolone Core and their antioxidant activity | |
| Mishina et al. | A new synthesis of 2-aminoindoles and 6-aminopyrrolo [3, 2-d] pyrimidines from π-deficient 1, 2-dihaloarenes and geminal enediamines | |
| Okuda et al. | Polycyclic N‐heterocyclic compounds, part 69: Synthesis of 5‐amino‐1, 2‐dihydro [1] benzofuro [3, 2‐d] furo [2, 3‐b] pyridines and their transformations to related compounds |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |