CN113173951B - 一种亲核去芳构化合成3,4-二氢嘧啶酮的方法 - Google Patents
一种亲核去芳构化合成3,4-二氢嘧啶酮的方法 Download PDFInfo
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- QGKGASXQTBQINX-UHFFFAOYSA-N 3,4-dihydro-1h-pyrimidin-2-one Chemical compound O=C1NCC=CN1 QGKGASXQTBQINX-UHFFFAOYSA-N 0.000 title claims abstract description 32
- 238000000034 method Methods 0.000 title claims abstract description 16
- 230000000269 nucleophilic effect Effects 0.000 title claims abstract description 12
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 42
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000003054 catalyst Substances 0.000 claims abstract description 14
- 150000008301 phosphite esters Chemical class 0.000 claims abstract description 8
- 239000000758 substrate Substances 0.000 claims abstract description 8
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 239000012434 nucleophilic reagent Substances 0.000 claims abstract description 4
- 230000035484 reaction time Effects 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 57
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- -1 3, 4-dihydropyrimidinone compound Chemical class 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- DUNKXUFBGCUVQW-UHFFFAOYSA-J zirconium tetrachloride Chemical group Cl[Zr](Cl)(Cl)Cl DUNKXUFBGCUVQW-UHFFFAOYSA-J 0.000 claims description 4
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- 229940125782 compound 2 Drugs 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 abstract description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 60
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 59
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 48
- 229940087646 methanolamine Drugs 0.000 description 16
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 14
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- 238000002844 melting Methods 0.000 description 14
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- 238000004679 31P NMR spectroscopy Methods 0.000 description 12
- 238000000746 purification Methods 0.000 description 12
- PCBNXKFYNJHJKY-UHFFFAOYSA-N 5-methyl-6-phenyl-1h-pyrimidin-2-one Chemical compound C1=NC(=O)NC(C=2C=CC=CC=2)=C1C PCBNXKFYNJHJKY-UHFFFAOYSA-N 0.000 description 11
- CZHYKKAKFWLGJO-UHFFFAOYSA-N dimethyl phosphite Chemical compound COP([O-])OC CZHYKKAKFWLGJO-UHFFFAOYSA-N 0.000 description 10
- 229910007926 ZrCl Inorganic materials 0.000 description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- NQPJDJVGBDHCAD-UHFFFAOYSA-N 1,3-diazinan-2-one Chemical compound OC1=NCCCN1 NQPJDJVGBDHCAD-UHFFFAOYSA-N 0.000 description 1
- 150000008319 1H-pyrimidin-2-ones Chemical class 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 108090000312 Calcium Channels Proteins 0.000 description 1
- 102000003922 Calcium Channels Human genes 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 229910007932 ZrCl4 Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229910052927 chalcanthite Inorganic materials 0.000 description 1
- 229940011182 cobalt acetate Drugs 0.000 description 1
- GVPFVAHMJGGAJG-UHFFFAOYSA-L cobalt dichloride Chemical compound [Cl-].[Cl-].[Co+2] GVPFVAHMJGGAJG-UHFFFAOYSA-L 0.000 description 1
- KTVIXTQDYHMGHF-UHFFFAOYSA-L cobalt(2+) sulfate Chemical compound [Co+2].[O-]S([O-])(=O)=O KTVIXTQDYHMGHF-UHFFFAOYSA-L 0.000 description 1
- QAHREYKOYSIQPH-UHFFFAOYSA-L cobalt(II) acetate Chemical compound [Co+2].CC([O-])=O.CC([O-])=O QAHREYKOYSIQPH-UHFFFAOYSA-L 0.000 description 1
- 229910000365 copper sulfate Inorganic materials 0.000 description 1
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 description 1
- NFORZJQPTUSMRL-UHFFFAOYSA-N dipropan-2-yl hydrogen phosphite Chemical compound CC(C)OP(O)OC(C)C NFORZJQPTUSMRL-UHFFFAOYSA-N 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- RUTXIHLAWFEWGM-UHFFFAOYSA-H iron(3+) sulfate Chemical compound [Fe+3].[Fe+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O RUTXIHLAWFEWGM-UHFFFAOYSA-H 0.000 description 1
- 229910000360 iron(III) sulfate Inorganic materials 0.000 description 1
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 1
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000006452 multicomponent reaction Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000009901 transfer hydrogenation reaction Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 229940102001 zinc bromide Drugs 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6509—Six-membered rings
- C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供一种亲核去芳构化合成3,4‑二氢嘧啶酮的方法,在催化剂作用下,采用亚磷酸酯作为亲核试剂,对简单易得2‑羟基嘧啶进行亲核去芳构化反应得到含有磷酸酯取代基的二氢嘧啶酮衍生物。反应在室温~100摄氏度,常规有机溶剂中进行,底物和催化剂的比例是1000:1~10:1,反应时间8~24小时。本发明操作简便易行,反应条件温和,产率高。
Description
技术领域
本发明涉及一种通过对2-羟基嘧啶进行亲核去芳构化,来合成3,4-二氢嘧啶酮化合物的方法。
技术背景
二氢嘧啶酮类化合物在药物化学中应用非常广泛,是一类重要的优势结构,包括抗癌活性、钙通道抑制、抗炎活性、抗菌活性等[(a)Biginelli,P.Gazz.Chim.Ital.1893,23,360.(b)Kappe,C.O.Acc.Chem.Res.2000,33,879.(c)Kappe,C.O.QSAR Comb.Sci.2003,22,630]。其嘧啶环C4位的手性中心对该类化合物的生物活性和药效具有举足轻重的影响。目前,主要依赖不对称Biginelli多组分反应来合成此类化合物[(a)Gong,L.-Z.;Chen,X.-H.;Xu,X.-Y.Chem.Eur.J.2007,13,8920.(b)Heravi,M.M.;Asadi,S.;Lashkariani,B.M.Mol Divers 2013,17,389]。但是,该反应受限于较窄的底物适用范围,只能构建4位为芳基或者烷基取代的二氢嘧啶酮类化合物。因此,发展新的合成方法以实现手性二氢嘧啶酮类化合物多样性制备与新结构的创制,特别是目前研究中较少涉及的C4位为烷基或杂原子取代的二氢嘧啶酮化合物,是很有实用价值的研究课题,对于新药的发现具有重要意义。
2018年,周永贵课题组[Feng,G.-S.;Chen,M.-W.;Shi,L.;Zhou,Y.-G.Angew.Chem.Int.Ed.2018,57,5853]以钯为催化剂,以氢气为氢源,实现了对羟基嘧啶的不对称氢化,以高收率和高对映选择性得到了四氢嘧啶酮和二氢嘧啶酮衍生物,展示了一条合成二氢嘧啶酮的新途径。2019年,时磊等人[Meng,F.J.;Shi,L.;Feng,G.S.;Sun,L.andZhou,Y.G.J.Org.Chem.2019,84,4435.]又以手性磷酸为催化剂,以汉栖酯为氢源对羟基嘧啶进行不对称转移氢化得到二氢嘧啶酮,产率和对映选择性较高,合成了手性中心连有烷基取代基的二氢嘧啶酮衍生物。该工作的主要原理是羟基嘧啶存在酮式异构体,降低了其芳香性,从而可以使去芳构化反应进行。本专利采用亚磷酸酯为亲核试剂对羟基嘧啶进行进攻,通过对羟基嘧啶的亲核去芳构化,高产率合成含有磷酸酯取代基的二氢嘧啶酮衍生物。
发明内容
本发明的目的是提供一种亲核去芳构化合成3,4-二氢嘧啶酮的方法,是一种由2-羟基嘧啶来合成3,4-二氢嘧啶酮化合物的方法。本发明操作简便实用,原料易得,产率好,且反应具有绿色原子经济性,环境友好等优点。
为实现上述目的,本发明的技术方案如下:
一种亲核去芳构化合成3,4-二氢嘧啶酮的方法,在催化剂作用下,以2-羟基嘧啶1为底物,采用亚磷酸酯为亲核试剂,对简单易得2-羟基嘧啶1进行亲核去芳构化反应,合成含有磷酸酯取代基的二氢嘧啶酮衍生物,即3,4-二氢嘧啶酮化合物2,实现了2-羟基嘧啶1的亲核去芳构化。
其合成路线如下:
式中:
所述R1和R2各自独立为C1-C7的烷基、苯基或含有取代基的苯环,取代基为Cl、F、Me、MeO中的一种或两种或三种取代基;
所述R3为Me、Et、Bn、iPr、tBu中的一种;
所述催化剂为乙酸、苯甲酸、对甲苯磺酸、醋酸钴、氯化钴、硫酸铜、氯化铜、三氟甲磺酸酮、碘化亚铜、硫酸铁、三氯化铝、氯化锌、溴化锌、四氯化锆中的一种或两种以上的混合,其中优选为四氯化锆。
基于以上技术方案,优选的,反应步骤为:向2-羟基嘧啶、亚磷酸酯和的催化剂的中加入有机溶剂,搅拌反应后,直接柱层析得到相应的3,4-二氢嘧啶酮化合物。
基于以上技术方案,优选的,反应中底物2-羟基嘧啶1与催化剂的摩尔比为1000:1~10:1(即催化剂的使用量为底物2-羟基嘧啶1的0.1~10mol%),优选为1000:1~20:1(即催化剂的使用量为底物2-羟基嘧啶1的0.1~5mol%)。
基于以上技术方案,优选的,反应中亚磷酸酯的使用量和2-羟基嘧啶1的摩尔比为1:1~2:1,优选为1.5:1。
基于以上技术方案,优选的,反应所用的有机溶剂为苯,甲苯,二甲苯,均三甲苯,氯苯,二氯甲烷,三氯甲烷,乙腈,乙酸乙酯,乙酸甲酯,甲醇,乙醇,正丁醇,异丙醇,乙醚,叔丁基甲基醚,四氢呋喃,二氧六环,石油醚,正己烷,环己烷中的一种或两种以上的混合。
基于以上技术方案,优选的,所用反应温度为室温~100摄氏度。
基于以上技术方案,优选的,所用反应时间为8~24小时。
本发明具有以下优点
1.原料简单易得。
2.反应活性高,原料转化完全,产率高,分离方便。
3.反应条件温和。
具体实施方式
下面通过实施例详述本发明,但本发明并不限于下述的实施例。
下述实施例中5-甲基-4-苯基-2-羟基嘧啶(1a)参照G.S.Feng,M.W.Chen,L.Shiand Y.G.Zhou,Angew.Chem.Int.Ed.,2018,57,5853-5857来制备;4,5-二(取代苯基)-2-羟基嘧啶(1h-1l)参照J.J.Chen,U.S.Patent 10,715,666,2004来制备。
实施例1
向反应瓶中先后加入0.2m mol 5-甲基-4-苯基-2-羟基嘧啶(1a)、亚磷酸二甲酯(1.5eq.)和ZrCl4(3mol%),再加入2毫升THF。室温下搅拌反应24h后,直接柱层析提纯得到目标产物(流动相为二氯甲烷,甲醇和三乙胺,体积比为30:1:1),收率98%。
反应式如下:
所得二氢嘧啶酮2a为白色固体,熔点:89-91℃,Rf=0.4(二氯甲烷/甲醇/三乙胺=30/1/1)。1H NMR(400MHz,DMSO-d6)δ8.32(s,1H),7.46–7.34(m,3H),7.30–7.24(m,2H),7.05(q,J=1.9Hz,1H),4.18(dd,J=8.4,3.5Hz,1H),3.73(dd,J=14.7,10.2Hz,6H),1.68(d,J=3.4Hz,3H).13C NMR(101MHz,DMSO-d6)δ159.44,153.91,136.29,134.77,134.67,129.75,121.63,114.57,114.39,98.39,54.08(d,J=7.1Hz),54.08(d,J=149.8Hz),53.04(d,J=7.3Hz),16.88.31P NMR(162MHz,DMSO-d6)δ22.39。分子式为C13H17N2O4P,[M+H]+计算值:296.0873,测定值:296.0875。
实施例2
向反应瓶中先后加入0.2m mol 5-甲基-4-苯基-2-羟基嘧啶(1a)、亚磷酸二甲酯(1.5eq.)和TsOH(10mol%),再加入2毫升DCM。室温下搅拌反应24h后,直接柱层析提纯得到目标产物(流动相为二氯甲烷,甲醇和三乙胺,体积比为30:1:1),收率29%。
反应式如下:
实施例3
向反应瓶中先后加入0.2m mol 5-甲基-4-苯基-2-羟基嘧啶(1a)、亚磷酸二甲酯(1.5eq.)和CuSO4·5H2O(10mol%),再加入2毫升DCM。室温下搅拌反应24h后,直接柱层析提纯得到目标产物(流动相为二氯甲烷,甲醇和三乙胺,体积比为30:1:1),收率20%。
反应式如下:
实施例4
向反应瓶中先后加入0.2m mol 5-甲基-4-苯基-2-羟基嘧啶(1a)、亚磷酸二甲酯(1.5eq.)和CoSO4·6H2O(10mol%),再加入2毫升DCM。室温下搅拌反应24h后,直接柱层析提纯得到目标产物(流动相为二氯甲烷,甲醇和三乙胺,体积比为30:1:1),收率29%。
反应式如下:
实施例5
向反应瓶中先后加入0.2m mol 5-甲基-4-苯基-2-羟基嘧啶(1a)、亚磷酸二甲酯(1.5eq.)和ZrCl4(3mol%),再加入2毫升DCM。室温下搅拌反应24h后,直接柱层析提纯得到目标产物(流动相为二氯甲烷,甲醇和三乙胺,体积比为30:1:1),收率44%。
反应式如下:
实施例6
向反应瓶中先后加入0.2m mol 5-甲基-4-苯基-2-羟基嘧啶(1a)、亚磷酸二甲酯(1.5eq.)和ZrCl4(3mol%),再加入2毫升甲醇。室温下搅拌反应24h后,直接柱层析提纯得到目标产物(流动相为二氯甲烷,甲醇和三乙胺,体积比为30:1:1),收率76%。
反应式如下:
实施例7
向反应瓶中先后加入0.2m mol 5-甲基-4-苯基-2-羟基嘧啶(1a)、亚磷酸二甲酯(1.5eq.)和ZrCl4(3mol%),再加入2毫升乙酸乙酯。室温下搅拌反应24h后,直接柱层析提纯得到目标产物(流动相为二氯甲烷,甲醇和三乙胺,体积比为30:1:1),收率59%。
反应式如下:
实施例8
向反应瓶中先后加入0.2m mol 5-甲基-4-苯基-2-羟基嘧啶(1a)、亚磷酸二甲酯(1.5eq.)和ZrCl4(3mol%),再加入2毫升甲苯。室温下搅拌反应24h后,直接柱层析提纯得到目标产物(流动相为二氯甲烷,甲醇和三乙胺,体积比为30:1:1),收率31%。
反应式如下:
实施例9
向反应瓶中先后加入0.2m mol 5-甲基-4-(取代苯基)-2-羟基嘧啶(1b-1g)、亚磷酸二甲酯(1.5eq.)和ZrCl4(3mol%),再加入2毫升THF。室温下搅拌反应24h后,直接柱层析提纯得到目标产物(流动相为二氯甲烷,甲醇和三乙胺,体积比为30:1:1)。
反应式如下:
所得二氢嘧啶酮2b为白色固体,收率99%,熔点:182-183℃,Rf=4.16(dd,J=8.4,3.5Hz,1H),3.73(dd,J=14.8,10.2Hz,5H),2.33(s,3H),1.68(d,J=3.4Hz,3H).13C NMR(101MHz,DMSO-d6)δ153.91,137.87,134.95,129.71,129.41,128.58,126.37,98.17,54.11(d,J=149.1Hz),54.08(d,J=6.6Hz),53.02(d,J=7.1Hz),21.42,16.83.31P NMR(162MHz,DMSO-d6)δ23.22.分子式为C14H19N2O4P,[M+H]+计算值:311.1152,测定值:311.1157。
所得二氢嘧啶酮2c为白色固体,收率:98%,熔点:185-187℃,Rf Hz,6H),2.33(s,3H),1.68(d,J=3.4Hz,3H).13C NMR(101MHz,DMSO-d6)δ153.97,138.15,134.93,134.83,132.18,132.14,129.24,129.12,129.09,97.91(d,J=4.4Hz),54.14(d,J=149.1Hz),54.06(d,J=6.7Hz),53.02(d,J=7.0Hz),21.29,16.86(d,J=2.5Hz).31P NMR(162MHz,DMSO-d6)δ23.13.分子式为C14H19N2O4P,[M+H]+计算值:311.1152,测定值:311.1156。
所得二氢嘧啶酮2d为白色固体,收率:95%,熔点:116-117℃,Rf Hz,1H),3.73(dd,J=13.0,10.3Hz,6H),1.68(d,J=3.5Hz,3H).13C NMR(101MHz,DMSO-d6)δ153.81,136.93,133.63,133.35,130.63,128.91,128.80,128.16,99.47,54.77,54.09(d,J=6.7Hz),53.17(d,J=24.0Hz),16.70.31P NMR(162MHz,DMSO-d6)δ23.18.分子式为C13H16ClN2O4P,[M+H]+计算值:331.0424,测定值:331.0428。
所得二氢嘧啶酮2e为白色固体,收率:94%,熔点:91-94℃,Rf=Hz,1H),3.73(dd,J=13.0,10.3Hz,6H),1.68(d,J=3.5Hz,3H).13C NMR(101MHz,DMSO-d6)δ153.85,133.94,133.85,133.79,133.76,133.36,131.19,131.16,128.77,99.04(d,J=4.2Hz),54.08(d,J=149.3Hz),54.06(d,J=7.0Hz),53.07(d,J=6.7Hz),16.71.31P NMR(162MHz,DMSO-d6)δ23.14.分子式为C13H16ClN2O4P,[M+H]+计算值:331.0424,测定值:331.0425。
2H),4.17(dd,J=8.5,3.5Hz,1H),3.78(s,3H),3.73(dd,J=14.0,10.3Hz,6H),1.70(d,J=3.4Hz,3H).13C NMR(101MHz,DMSO-d6)δ159.45,153.91,136.28(d,J=4.2Hz),134.74(d,J=9.4Hz),129.76,121.64,114.58,114.41,98.40(d,J=4.3Hz),55.54,54.09(d,J=7.1Hz),54.08(d,J=149.4Hz),53.04(d,J=7.0Hz),16.89.31P NMR(162MHz,DMSO-d6)δ23.32.分子式为C14H19N2O4P,[M+H]+计算值:326.0981,测定值:326.0983。
(dd,J=9.3,3.5Hz,1H),3.73(dd,J=11.9,10.3Hz,6H),1.71(d,J=3.5Hz,3H).13C NMR(101MHz,DMSO-d6)δ163.76(d,J=13.5Hz),161.30(d,J=14.8Hz),153.81,138.19(td,J=9.9,3.8Hz),132.86(d,J=8.7Hz),112.94–112.45(m),104.43(t,J=25.8Hz),100.28(d,J=4.3Hz),54.12(d,J=6.8Hz),54.00(d,J=149.5Hz),53.13(d,J=7.0Hz),16.64(d,J=2.4Hz).分子式为C13H16F2N2O4P,[M+H]+计算值:333.0809,测定值:333.0812。
实施例10
向反应瓶中先后加入0.2m mol 4,5-二(取代苯基)-2-羟基嘧啶(1h-1l)、亚磷酸二甲酯(1.5eq.)和ZrCl4(3mol%),再加入2毫升THF。室温下搅拌反应24h后,直接柱层析提纯得到目标产物(流动相为二氯甲烷,甲醇和三乙胺,体积比为30:1:1)。
所得二氢嘧啶酮2h为白色固体,产率:94%,熔点:152-154℃Rf=0.41H),3.62(dd,J=31.8,10.3Hz,6H).13C NMR(101MHz,DMSO-d6)δ154.24,138.09(d,J=1.8Hz),137.95,137.86,135.15(d,J=3.1Hz),130.29,129.72,129.69,128.85,128.58,128.18,126.45,103.99,54.08(d,J=151.0Hz),53.88(d,J=6.9Hz),53.04(d,J=7.0Hz).31P NMR(162MHz,DMSO-d6)δ22.15.分子式为C18H19N2O4P,[M+H]+计算值:359.1062,测定值:359.1064。
所得二氢嘧啶酮2i为白色固体,产率:91%,熔点:173-175℃,Rf=0.4(二氯甲烷/甲醇/三乙胺=30/1/1)。1H NMR(400MHz,DMSO-d6)δ8.632.17(d,J=29.7Hz,6H).13C NMR(101MHz,DMSO-d6)δ154.29,138.13,137.46(d,J=8.0Hz),135.39,135.33(d,J=2.3Hz),132.37(d,J=3.3Hz),130.09,129.58,129.16,128.85,103.38,54.11(d,J=150.7Hz),53.89(d,J=6.6Hz),53.01(d,J=6.8Hz),21.25,21.09.31PNMR(162MHz,DMSO-d6)δ25.19.分子式为C20H23N2O4P,[M+H]+计算值:387.1468,测定值:387.1470。
所得二氢嘧啶酮2j为白色固体,产率:89%,熔点:172-173℃,Rf=1H),3.62(dd,J=27.0,10.3Hz,6H),2.22(d,J=23.0Hz,6H).13C NMR(101MHz,DMSO-d6)δ154.25,138.02(d,J=2.4Hz),137.82,137.74,137.60,137.01,135.14,135.11,130.61,130.04,129.42,128.32,127.92,127.55,127.09,126.93,103.84,54.96–53.23(m),53.87(d,J=7.1Hz),53.00(d,J=6.7Hz),21.49,21.39.31P NMR(162MHz,DMSO-d6)δ25.09.分子式为C20H23N2O4P,[M+H]+计算值:387.1468,测定值:387.1472。
所得二氢嘧啶酮2k为白色固体,产率:90%,熔点:203-206℃,7.34(d,J=8.3Hz,2H),7.17(dt,J=16.2,8.4Hz,6H),4.54(dd,J=8.7,3.9Hz,1H),3.63(dd,J=28.2,10.3Hz,6H).13C NMR(101MHz,DMSO-d6)δ154.00,137.45(d,J=8.6Hz),136.77,133.63,132.12,131.64,131.21,128.83,128.35,103.26,54.03(d,J=6.9Hz),53.67(d,J=151.3Hz),53.08(d,J=6.8Hz).31P NMR(162MHz,DMSO-d6)δ24.76.分子式为C18H17ClN2O4P,[M+H]+计算值:427.0182,测定值:427.0187。
所得二氢嘧啶酮2l为白色固体,产率:85%,熔点:202-203℃,Rf=8.8,3.8Hz,1H),3.63(dd,J=27.9,10.4Hz,6H).13C NMR(101MHz,DMSO-d6)δ154.22,138.11,137.96,137.88,135.16,135.12,130.28,129.72,128.86,128.59,128.18,126.44,103.93,54.03(d,J=151.0Hz),53.90(d,J=6.6Hz),53.03(d,J=7.0Hz).分子式为C18H17ClN2O4P,[M+H]+计算值:427.0182,测定值:427.0186。
实施例11
向反应瓶中先后加入0.2m mol 5-甲基-4-苯基-2-羟基嘧啶(1a)、亚磷酸二乙酯(1.5eq.)和ZrCl4(3mol%),再加入2毫升THF。室温下搅拌反应24h后,直接柱层析提纯得到目标产物(流动相为二氯甲烷,甲醇和三乙胺,体积比为30:1:1),收率95%。
反应式如下:
所得二氢嘧啶酮2m为白色固体,熔点:156-158℃,Rf=0.4(二氯甲烷/甲醇/三乙胺=30/1/1).1H NMR(400MHz,DMSO-d6)δ8.29(s,1H),7.39(dq,J=12.8,7.0Hz,3H),7.30–7.20(m,2H),6.95(s,1H),4.19–3.99(m,5H),1.68(d,J=3.4Hz,3H),1.27(dt,J=8.5,7.0Hz,6H).13C NMR(101MHz,DMSO-d6)δ153.90,135.13(d,J=3.8Hz),134.80,134.71,129.21,129.18,128.69,98.52,98.47,63.04(d,J=7.0Hz),62.23(d,J=7.2Hz),54.66(d,J=150.2Hz),17.05(d,J=5.0Hz),16.90,16.85.31P NMR(162MHz,DMSO-d6)δ22.39.分子式为C15H21N2O4P,[M+H]+计算值:325.0954,测定值:325.0950。
实施例12
向反应瓶中先后加入0.2m mol 5-甲基-4-苯基-2-羟基嘧啶(1a)、亚磷酸二异丙酯(1.5eq.)和ZrCl4(3mol%),再加入2毫升THF。室温下搅拌反应24h后,直接柱层析提纯得到目标产物(流动相为二氯甲烷,甲醇和三乙胺,体积比为30:1:1),收率64%。
所得二氢嘧啶酮2n为白色固体,熔点:122-124℃,Rf=0.4(二氯甲烷/甲醇/三乙胺=30/1/1).1H NMR(400MHz,DMSO-d6)δ8.27(s,1H),7.45–7.34(m,3H),7.29–7.22(m,2H),6.78–6.69(m,1H),4.63(ddq,J=12.6,9.9,6.2Hz,2H),4.00(dd,J=8.6,3.4Hz,1H),1.68(d,J=3.4Hz,3H),1.33–1.25(m,12H).13C NMR(101MHz,DMSO-d6)δ153.66,135.25,134.51,134.43(d,J=4.1Hz),129.23,129.20,128.69,98.58,71.41(d,J=7.6Hz),70.80(d,J=8.0Hz),55.58(d,J=153.7Hz),24.43(dd,J=44.5,4.0Hz),24.36(t,J=4.7Hz),17.06.31P NMR(162MHz,DMSO-d6)δ20.54.分子式为C17H25N2O4P,[M+H]+计算值:356.1623,测定值:353.1623。
本发明对2-羟基嘧啶的亲核去芳构化得到相应的3,4-二氢嘧啶酮化合物,其产率可达99%。本发明操作简便实用,产率好,且环境友好绿色,反应条件温和,具有潜在的实际应用价值。
Claims (6)
2.如权利要求1所述的方法,其特征在于:反应步骤为:
向2-羟基嘧啶1、亚磷酸酯和催化剂中加入有机溶剂,反应得到3,4-二氢嘧啶酮化合物。
3.如权利要求1或2所述的方法,其特征在于:所述底物与催化剂的摩尔比为1000:1~10:1。
4.如权利要求1或2所述的方法,其特征在于:亚磷酸酯和2-羟基嘧啶1的摩尔比为1:1~2:1。
5.如权利要求1或2所述的方法,其特征在于:反应温度为室温~100摄氏度。
6.如权利要求1或2所述的方法,其特征在于:反应时间为8~24小时。
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The reaction of quinazolinones with phosphorus(III) reagents;Mulvey, Dennis M. et al;《Synthesis》;19811231;第7卷;第533-4页 * |
ZrCl4-catalyzed nucleophilic dearomatization of 2-hydroxy-pyrimidines: A concise synthesis of novel 3,4-dihydropyrimidin-2(1H)-ones containing a phosphonic ester group;Li, Kang-rui et al;《Tetrahedron Letters》;20210504;第73卷;第153149页 * |
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