CN117003708A - 一种手性α四取代的噁唑-4(5H)-酮的制备方法 - Google Patents
一种手性α四取代的噁唑-4(5H)-酮的制备方法 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- KCOPAESEGCGTKM-UHFFFAOYSA-N 1,3-oxazol-4-one Chemical class O=C1COC=N1 KCOPAESEGCGTKM-UHFFFAOYSA-N 0.000 title claims description 18
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 76
- 239000003446 ligand Substances 0.000 claims abstract description 43
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 42
- 238000006243 chemical reaction Methods 0.000 claims abstract description 41
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 38
- 239000002904 solvent Substances 0.000 claims abstract description 24
- 239000003054 catalyst Substances 0.000 claims abstract description 21
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 19
- 230000001681 protective effect Effects 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 42
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 claims description 39
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 29
- 229910000026 rubidium carbonate Inorganic materials 0.000 claims description 29
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 26
- 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 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- WPFGFHJALYCVMO-UHFFFAOYSA-L rubidium carbonate Chemical compound [Rb+].[Rb+].[O-]C([O-])=O WPFGFHJALYCVMO-UHFFFAOYSA-L 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000001041 indolyl group Chemical group 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 2
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- -1 ketocarbonyl Chemical group 0.000 claims description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 2
- PBDBXAQKXCXZCJ-UHFFFAOYSA-L palladium(2+);2,2,2-trifluoroacetate Chemical compound [Pd+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F PBDBXAQKXCXZCJ-UHFFFAOYSA-L 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- JBEPFZCYCKRHTN-UHFFFAOYSA-N C(=O)O.C12CC3CC(CC(C1)C3)C2 Chemical compound C(=O)O.C12CC3CC(CC(C1)C3)C2 JBEPFZCYCKRHTN-UHFFFAOYSA-N 0.000 claims 1
- 239000000758 substrate Substances 0.000 abstract description 8
- 239000003513 alkali Substances 0.000 abstract description 7
- 239000000654 additive Substances 0.000 abstract description 2
- 125000000524 functional group Chemical group 0.000 abstract description 2
- 238000001308 synthesis method Methods 0.000 abstract description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 32
- 239000000047 product Substances 0.000 description 32
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 20
- 238000004128 high performance liquid chromatography Methods 0.000 description 20
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 238000004587 chromatography analysis Methods 0.000 description 10
- 239000012043 crude product Substances 0.000 description 10
- 238000003818 flash chromatography Methods 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- 239000007858 starting material Substances 0.000 description 10
- 230000000052 comparative effect Effects 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 238000012512 characterization method Methods 0.000 description 4
- 238000006254 arylation reaction Methods 0.000 description 3
- 150000001728 carbonyl compounds Chemical class 0.000 description 3
- 150000004795 grignard reagents Chemical class 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 150000002940 palladium Chemical class 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 2
- 150000001499 aryl bromides Chemical class 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000005935 nucleophilic addition reaction Methods 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 238000005882 aldol condensation reaction Methods 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 238000005937 allylation reaction Methods 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000005574 benzylation reaction Methods 0.000 description 1
- 230000021523 carboxylation Effects 0.000 description 1
- 238000006473 carboxylation reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000007333 cyanation reaction Methods 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/36—One oxygen atom
- C07D263/40—One oxygen atom attached in position 4
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
- B01J31/2442—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
- B01J2231/4205—C-C cross-coupling, e.g. metal catalyzed or Friedel-Crafts type
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/82—Metals of the platinum group
- B01J2531/824—Palladium
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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Abstract
本发明公开了一种手性α四取代的噁唑‑4(5H)‑酮的制备方法,在保护气氛下,将溴化物与噁唑‑4(5H)‑酮衍生物在钯催化剂、手性膦配体、碱以及溶剂的存在下反应,即可得到所述手性α四取代的噁唑‑4(5H)‑酮。本发明通过反应底物的选择,并在特定手性配体及钯催化剂的作用下,可合成ee值高达93%的手性α四取代的噁唑‑4(5H)‑酮,且反应产率高;上述合成方法易操作,无需添加额外的添加剂,反应简单高效,且底物适用范围广,官能团兼容性强,可用于制备不同种类的手性α四取代的噁唑‑4(5H)‑酮。
Description
技术领域
本发明涉及有机合成领域,具体涉及一种手性α四取代的噁唑-4(5H)-酮的制备方法。
背景技术
α-芳基-α-羟基羧酸是一种广泛存在于天然产物和药理活性分子中的结构[(a)Chem.Soc.Rev.,2009,38,2093.(b)Org.Biomol.Chem.,2007,5,406],目前这类结构的立体选择性地合成主要集中在对羰基化合物的亲核加成反应上,比如酮的α-氰化[J.Am.Chem.Soc.,2001,123,6195]、α-酮酯与羰基化合物的羟醛缩合反应[J.Am.Chem.Soc.,2008,130,5654]、手性辅助试剂控制的Grignard试剂对羰基化合物的亲核加成[Tetrahedron Lett.,2006,47,7067]、酮的还原羧化[Chem.Commun.,2009,2009,7297]等。但迄今为止,α-羟基羧酸衍生物直接实现不对称α-芳基化反应的策略还未见有报道。
噁唑-4(5H)-酮衍生物可以作为此类反应策略中的亲核试剂,通过不对称α-芳基化反应得到5,5-二取代噁唑-4-酮类化合物,这类化合物可以通过温和条件一步转化为具有光学活性的α-羟基羧酸衍生物。此前,此类底物的α位修饰主要集中在烷基化、烯丙基化、苄基化等反应[(a)Adv.Syn.Catal.,2014,356,3777.(b)J.Org.Chem.,2016,81,11916.(c)Adv.Syn.Catal.,2013,355,1505.(d)Angew.Chem.Int.Ed.,2012,51,6480.(e)Chem.Sci.,2015,6,4912]。但目前为止,此类底物的不对称α-芳基化反应策略此前未见有报道。
发明内容
本发明提供了一种手性α四取代的噁唑-4(5H)-酮的制备方法,通过反应底物的选择,并在特定手性配体及钯催化剂的作用下,可合成ee值高达93%的手性α四取代的噁唑-4(5H)-酮,且反应产率高。
为了解决上述技术问题,本发明提供以下技术方案:
本发明提供了一种手性α四取代的噁唑-4(5H)-酮的制备方法,在保护气氛下,将式(I)所示的化合物与式(II)所示的化合物在钯催化剂、手性膦配体、碱以及溶剂的存在下反应,得到式(III)所示的手性α四取代的噁唑-4(5H)-酮;
上述式(I)~式(III)的结构如下:
其中,A选自取代或未取代的苯基、取代或未取代的噻吩基、取代或未取代的萘基、取代或未取代的吲哚基中的一种;
R1选自取代或未取代的C1-6烷基、取代或未取代的苄基中的一种;
Ar1为取代或未取代的苯基;
取代或未取代表示该基团被一个或多个取代基取代或未被取代,所述取代基选自卤素、C1-6烷基、C1-6烷氧基、三氟甲基、酮羰基、芳基中的一种。
所述手性膦配体选自以下结构中的一种:
进一步地,在保护气氛下,先将钯催化剂与手性膦配体在溶剂中混合,形成催化剂[Pd]/L*溶液,然后将式(I)所示的化合物、式(II)所示的化合物及碱加入催化剂[Pd]/L*溶液中反应,得到所述手性α四取代的噁唑-4(5H)-酮;所述保护气氛由氮气和/或氩气组成。
进一步地,A更优选为苯基、卤素取代的苯基、C1-6烷基取代的苯基、噻吩基、萘基、酮羰基取代的吲哚基中的一种,R1更优选为C1-6烷基。
进一步地,所述手性膦配体更优选为式X1所示的化合物和/或式X2所示的化合物。
进一步地,所述钯催化剂选自醋酸钯、三氟乙酸钯、二氯二乙腈钯、氯化钯、金刚烷甲酸钯中的一种或多种;更优选为醋酸钯。
进一步地,所述碱选自碳酸钠、碳酸钾、碳酸铯、碳酸铷、磷酸钾中的一种或多种;更优选为碳酸铷。
进一步地,所述溶剂选自二氯甲烷、2-甲基四氢呋喃、四氢呋喃、三氟甲苯、甲苯、均三甲苯、氯苯、乙酸乙酯、正己烷、甲基叔丁基醚、苯甲醚、异丙醚、正丁醚、乙醚中的一种或多种;更优选为均三甲苯。
在本发明一些优选的实施例中,所述钯催化剂为醋酸钯,所述碱为碳酸铷,所述溶剂为均三甲苯。
进一步地,式(I)所示的化合物与式(II)所示的化合物、钯催化剂、手性膦配体、碱的投料摩尔比为1:1-2:0.025-0.1:0.03-0.2:1-2.5。
进一步地,所述反应的反应温度为20-100℃,更优选为20-50℃,反应时间为6-60h。
与现有技术相比,本发明的有益效果:
本发明通过反应底物的选择,并在特定手性配体及钯催化剂的作用下,可合成ee值高达93%的手性α四取代的噁唑-4(5H)-酮,且反应产率高;上述合成方法易操作,无需添加额外的添加剂,反应简单高效,且底物适用范围广,官能团兼容性强,可用于制备不同种类的手性α四取代的噁唑-4(5H)-酮,这类手性α四取代的噁唑-4(5H)-酮可一步转化为具有光学活性的α-羟基羧酸衍生物。
附图说明
图1为实施例2制备的产物3a的HPLC图;
图2为实施例3制备的产物3b的HPLC图;
图3为实施例4制备的产物3c的HPLC图;
图4为实施例5制备的产物3d的HPLC图;
图5为实施例6制备的产物3e的HPLC图;
图6为实施例7制备的产物3f的HPLC图;
图7为实施例8制备的产物3g的HPLC图;
图8为实施例9制备的产物3h的HPLC图;
图9为实施例10制备的产物3i的HPLC图;
图10为实施例11制备的产物3j的HPLC图。
具体实施方式
除非另有定义,本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的,不是旨在于限制本发明。本文所使用的术语“及/或”包括一个或多个相关的所列项目的任意的和所有的组合。本发明所述的“包括”或“包含”,意指其除所述组分外,还可以包括或包含其他组分。本发明所述的“包括”或“包含”,还可以替换为封闭式的“为”或“由......组成”。
下面结合具体实施例对本发明作进一步说明,以使本领域的技术人员可以更好地理解本发明并能予以实施,但所举实施例不作为对本发明的限定。
实施例1
本实施例涉及手性膦配体X1~X7的制备,其中X1~X6参考专利申请号为201910831293.0、201510107308.0和201310671902.3的中国专利以及文献[(a)Angew.Chem.Int.Ed.2020,59,4421.(b)Chem.Sci.,2020,11,6283]制备得到,X7直接购买获得,手性膦配体X1~X7的结构如下所示:
制备上述手性膦配体X3的反应流程如下:
具体制备过程如下:
在氮气保护下,在烘干的100mL三口烧瓶中加入搅拌子、镁屑(72mg,3.0mmol,3.0equiv.)和干燥的四氢呋喃(5mL),之后在65℃下向体系中滴加相应的芳基溴化物(2.0mmol,2.0equiv.)和引发剂1,2-二溴乙烷,待格氏试剂完全引发后,体系继续在65℃下搅拌两小时,然后在另一个干燥的100mL三口烧瓶中加入搅拌子、式4所示的化合物(1.0mmol,1.0equiv)和干燥的四氢呋喃(5mL),在-40℃下将格氏试剂逐滴滴入体系中,体系缓慢升至室温,继续搅拌8小时。TLC检测反应完全后,加入饱和氯化铵溶液(10mL)淬灭反应,使用乙酸乙酯(20mL)萃取三次,合并有机相,用无水硫酸钠干燥,旋蒸除去溶剂后,通过柱层析分离,得到式5所示的目标化合物。
在氮气保护下,在烘干的100mL三口烧瓶中加入搅拌子、式5所示的化合物(0.5mmol,1.0equiv.)和干燥的四氢呋喃(5mL),在-78℃下将正丁基锂(0.3mL,0.75mmol,1.5equiv.,2.5M正己烷溶液)逐滴滴入体系中,体系在-78℃下继续搅拌1小时,然后将碘甲烷(142mg,1.0mmol,2.0equiv.)滴入反应体系中,将反应液置于0℃下继续搅拌15分钟,TLC检测反应完全后,加入饱和氯化铵溶液(10mL)淬灭反应,使用乙酸乙酯(20mL)萃取三次,合并有机相,用无水硫酸钠干燥,旋蒸除去溶剂后,通过柱层析分离,得到目标手性膦配体X3(文献(a)中已公开)。
手性膦配体X1、X2、X4、X5通过改变上述芳基溴化物即可制备得到。
制备得到的手性膦配体X1测试表征数据如下:
1H NMR(400MHz,CDCl3)δ7.90(d,J=8.0Hz,2H),7.85(d,J=8.0Hz,2H),7.76(d,J=4.0Hz,1H),7.52-7.37(m,11H),7.26(s,1H),6.97(d,J=8.0Hz,1H),3.95(s,3H),3.89(s,3H),2.71(s,3H),2.03-2.00(m,3H),1.91-1.86(m,6H),1.75-1.52(m,21H),1.15(s,9H).
13C NMR(100MHz,CDCl3)δ149.9,145.9,140.8,140.5,140.3,140.0,133.7,132.9,131.5,130.3,128.2,127.6,126.7,125.8,125.7,125.3,124.2,124.0,119.6,110.7,77.2,71.7,71.3,58.9,56.1,55.9,41.9,41.8,41.7,37.9,37.6,36.8,36.8,31.3,28.8,28.7,24.3.
31P NMR(162MHz,CDCl3)δ15.64.
HRMS(ESI):m/z:[M+H]+Calcd for C60H69NO3PS:914.4736,found914.4736.
[α]D20=42.577(c=0.5,CHCl3).
熔点为121.4-122.0℃。
制备得到的手性膦配体X2测试表征数据如下:
1H NMR(400MHz,CDCl3)δ7.68(d,J=4.0Hz,1H),7.51(s,1H),7.37(s,2H),7.23(s,1H),6.96(d,J=12.0Hz,1H),6.64(d,J=4.0Hz,4H),6.47-6.46(m,2H),4.02(s,3H),3.91(s,3H),3.82(s,12H),2.70(s,3H),2.02-1.99(m,3H),1.90-1.86(m,6H),1.68-1.59(m,10H),1.50-1.36(m,11H),1.09(s,9H).
13C NMR(100MHz,CDCl3)δ161.0,150.0,146.0,143.5,141.3,141.2,141.0,130.4,124.7,124.5,124.4,119.5,110.7,105.5,99.2,71.4,71.0,58.9,56.2,56.0,55.4,42.0,41.8,41.7,37.9,37.7,36.9,36.9,36.8,36.6,31.2,28.8,28.8,28.7,28.7,24.3.
31P NMR(162MHz,CDCl3)δ15.94.
HRMS(ESI):m/z:[M+H]+Calcd for C56H73NO7PS:934.4845,found934.4846.
[α]D20=32.298(c=0.5,CHCl3).
熔点为145.6-145.8℃。
制备得到的手性膦配体X4测试表征数据如下:
1H NMR(400MHz,CDCl3)δ7.66-7.63(m,1H),7.58-7.56(m,1H),7.53-7.51(m,4H),7.44-7.40(m,6H),7.36-7.32(m,2H),7.27-7.26(m,1H),6.99(d,J=8.0Hz,1H),4.02(s,3H),3.93(s,3H),2.71(s,3H),2.04-2.00(m,3H),1.91-1.88(m,6H),1.69-1.65(m,10H),1.59-1.35(m,11H),1.10(s,9H).
13C NMR(100MHz,CDCl3)δ149.9,146.0,141.5,141.4,141.3,141.2,141.0,130.0,128.8,127.2,127.2,124.8,119.4,71.3,58.9,56.2,55.9,42.0,41.8,41.8,37.9,37.6,37.0,36.8,31.0,28.8,28.8,28.7,24.4,22.8.
31P NMR(162MHz,CDCl3)δ16.11.
HRMS(ESI):m/z:[M+H]+Calcd for C52H65NO3PS:814.4423,found814.4423.
[α]D20=43.457(c=0.5,CHCl3).
熔点为118.0-118.9℃。
制备得到的手性膦配体X5测试表征数据如下:
1H NMR(400MHz,CDCl3)δ7.55-7.54(m,1H),7.21(s,1H),6.78-6.75(m,1H),6.71(s,2H),6.60(s,1H),4.19-4.10(m,4H),4.00(s,3H),3.91(s,3H),2.60(s,3H),2.00-1.97(m,3H),1.88-1.84(m,6H),1.69-1.66(m,10H),1.57-1.46(m,11H),1.09(s,9H).
13C NMR(100MHz,CDCl3)δ149.8,145.8,142.6,142.4,141.9,141.6,133.4,125.1,124.1,121.0,119.4,116.2,110.8,70.6,70.2,64.4,64.3,58.7,56.1,56.0,41.9,41.8,41.8,41.7,37.8,37.6,36.9,36.9,36.6,30.8,28.9,28.8,28.8,28.7,24.5.
31P NMR(162MHz,CDCl3)δ15.91.
HRMS(ESI):m/z:[M+H]+Calcd for C42H59NO5PS:720.3852,found720.3851.
[α]D20=64.676(c=0.5,CHCl3).
熔点为111.3-111.4℃。
手性膦配体X6:根据文献(b)中所述的方法制备得到。
实施例2
本实施例提供了一种式3a所示的手性α四取代的噁唑-4(5H)-酮的制备,反应方程如下所示:
具体的制备过程如下:
在N2填充的手套箱内,在10mL史莱克管内加入Pd(OAc)2(6.6mg,0.03mmol,10mol%)、手性膦配体X1(33.0mg,0.036mmol,12mol%)和干燥的均三甲苯(3mL),室温下预搅拌1h。然后在手套箱内向封管内加入式1a所示的化合物(47.1mg,0.3mmol,1.0equiv)、式2a所示的化合物(91.4mg,0.45mmol,1.5equiv)和Rb2CO3(138.6mg,0.6mmol,2.0equiv)。N2保护下,反应体系在40℃油浴内搅拌反应48h,TLC确定原料反应完全。将溶剂旋干,粗产物用硅胶快速柱层析提纯(PE/EA展开剂)得到式3a所示的目标产物,产率为76%,ee值为93%。
对本实施例制备得到的产物进行测试表征,表征结果如下:
1H NMR(400MHz,CDCl3)δ8.33(d,J=8.0Hz,2H),7.72(t,J=8.0Hz,1H),7.59-7.55(m,4H),7.40-7.34(m,3H),1.95(s,3H).
13C NMR(100MHz,CDCl3)δ191.9,185.1,137.0,135.3,130.1,129.0,128.7,128.6,125.8,124.5,87.4,24.9.
HRMS(EI):m/z:[M]+Calcd for C16H13NO2:251.0946,found 251.0941.
[α]D20=-105.316(c=0.5,CHCl3).
HPLC测试条件:Daicel Chiralpak ODH色谱柱;正己烷/异丙醇=90/10,1.0mL/min,254nm;tr=7.65min(主峰),tr=8.51min(次峰).
实施例3
本实施例提供了一种式3b所示的手性α四取代的噁唑-4(5H)-酮的制备,反应方程如下所示:
具体的制备过程如下:
在N2填充的手套箱内,在10mL史莱克管内加入Pd(OAc)2(6.6mg,0.03mmol,10mol%)、手性膦配体X1(33.0mg,0.036mmol,12mol%)和干燥的均三甲苯(3mL),室温下预搅拌1h。然后在手套箱内向封管内加入式1b所示的化合物(69.9mg,0.3mmol,1.0equiv)、式2a所示的化合物(91.4mg,0.45mmol,1.5equiv)和Rb2CO3(138.6mg,0.6mmol,2.0equiv)。N2保护下,反应体系在40℃油浴内搅拌反应48h,TLC确定原料反应完全。将溶剂旋干,粗产物用硅胶快速柱层析提纯(PE/EA展开剂)得到式3b所示的目标产物,产率为86%,ee值为91%。
对本实施例制备得到的产物进行测试表征,表征结果如下:
1H NMR(400MHz,CDCl3)δ8.36(d,J=8.0Hz,2H),7.76-7.56(m,9H),7.44(t,J=8.0Hz,2H),7.37-7.33(m,1H),2.36-2.21(m,2H),1.46-1.38(m,2H),0.95(t,J=8.0Hz,3H).
13C NMR(100MHz,CDCl3)δ191.6,185.4,141.4,140.3,135.4,135.3,130.1,129.0,128.8,127.5,127.4,127.1,125.8,125.0,90.5,41.0,17.0,13.8.
HRMS(EI):m/z:[M]+Calcd for C24H21NO2:355.1572,found 355.1568.
[α]D20=-155.368(c=0.5,CHCl3).
熔点为142.0-142.9℃.
HPLC测试条件:Daicel Chiralpak OZ-3色谱柱;正己烷/异丙醇=90/10,1.0mL/min,254nm;tr=8.00min(次峰),tr=8.88min(主峰).
实施例4
本实施例提供了一种式3c所示的手性α四取代的噁唑-4(5H)-酮的制备,反应方程如下所示:
具体的制备过程如下:
在N2填充的手套箱内,在10mL史莱克管内加入Pd(OAc)2(6.6mg,0.03mmol,10mol%)、手性膦配体X1(33.0mg,0.036mmol,12mol%)和干燥的均三甲苯(3mL),室温下预搅拌1h。然后在手套箱内向封管内加入式1c所示的化合物(51.3mg,0.3mmol,1.0equiv)、式2a所示的化合物(91.4mg,0.45mmol,1.5equiv)和Rb2CO3(138.6mg,0.6mmol,2.0equiv)。N2保护下,反应体系在40℃油浴内搅拌反应48h,TLC确定原料反应完全。将溶剂旋干,粗产物用硅胶快速柱层析提纯(PE/EA展开剂)得到式3c所示的目标产物,产率为82%,ee值为89%。
对本实施例制备得到的产物进行测试表征,表征结果如下:
1H NMR(400MHz,CDCl3)δ8.34-8.31(m,2H),7.74-7.70(m,1H),7.59-7.55(m,2H),7.48-7.46(m,2H),7.18(d,J=8.0Hz,2H),2.33(s,3H),2.27-2.18(m,2H),1.39-1.33(m,2H),0.92(t,J=8.0Hz,3H).
13C NMR(100MHz,CDCl3)δ191.8,185.3,138.3,135.2,133.5,130.1,129.3,129.0,125.9,124.5,90.6,41.0,21.0,16.9,13.8.
HRMS(EI):m/z:[M]+Calcd for C19H19NO2:293.1416,found 293.1410.
[α]D20=-165.229(c=0.5,CHCl3).
HPLC测试条件:Daicel Chiralpak OJH色谱柱;正己烷/异丙醇=92/8,0.6mL/min,254nm;tr=13.28min(主峰),tr=16.23min(次峰).
实施例5
本实施例提供了一种式3d所示的手性α四取代的噁唑-4(5H)-酮的制备,反应方程如下所示:
在N2填充的手套箱内,在10mL史莱克管内加入Pd(OAc)2(6.6mg,0.03mmol,10mol%)、手性膦配体X1(33.0mg,0.036mmol,12mol%)和干燥的均三甲苯(3mL),室温下预搅拌1h。然后在手套箱内向封管内加入式1d所示的化合物(51.3mg,0.3mmol,1.0equiv)、式2a所示的化合物(91.4mg,0.45mmol,1.5equiv)和Rb2CO3(138.6mg,0.6mmol,2.0equiv)。N2保护下,反应体系在40℃油浴内搅拌反应48h,TLC确定原料反应完全。将溶剂旋干,粗产物用硅胶快速柱层析提纯(PE/EA展开剂)得到式3d所示的目标产物,产率为85%,ee值为92%。
对本实施例制备得到的产物进行测试表征,表征结果如下:
1H NMR(400MHz,CDCl3)δ8.36(d,J=8.0Hz,2H),7.85(s,1H),7.74(t,J=8.0Hz,1H),7.61-7.56(m,6H),7.48-7.43(m,3H),7.38-7.35(m,1H),2.34-2.27(m,2H),1.44-1.38(m,2H),0.95(t,J=8.0Hz,3H).
13C NMR(100MHz,CDCl3)δ191.5,185.3,141.8,140.6,137.0,135.3,130.1,129.0(overlap),128.8,127.5,127.3,127.2,125.7,123.4,123.3,90.5,41.3,16.9,13.7.
HRMS(EI):m/z:[M]+Calcd for C24H21NO2:355.1572,found 355.1566.
[α]D20=-125.222(c=0.5,CHCl3).
熔点为122.4-122.9℃.
HPLC测试条件:Daicel Chiralpak OZ-3色谱柱;正己烷/异丙醇=90/10,1.0mL/min,254nm;tr=7.08min(次峰),tr=9.08min(主峰).
实施例6
本实施例提供了一种式3e所示的手性α四取代的噁唑-4(5H)-酮的制备,反应方程如下所示:
在N2填充的手套箱内,在10mL史莱克管内加入Pd(OAc)2(6.6mg,0.03mmol,10mol%)、手性膦配体X1(33.0mg,0.036mmol,12mol%)和干燥的均三甲苯(3mL),室温下预搅拌1h。然后在手套箱内向封管内加入式1e所示的化合物(56.1mg,0.3mmol,1.0equiv)、式2a所示的化合物(91.4mg,0.45mmol,1.5equiv)和Rb2CO3(138.6mg,0.6mmol,2.0equiv)。N2保护下,反应体系在40℃油浴内搅拌反应48h,TLC确定原料反应完全。将溶剂旋干,粗产物用硅胶快速柱层析提纯(PE/EA展开剂)得到式3e所示的目标产物,产率为81%,ee值为91%。
对本实施例制备得到的产物进行测试表征,表征结果如下:
1HNMR(400MHz,CDCl3)δ8.31(d,J=8.0Hz,2H),7.70(t,J=8.0Hz,1H),7.57-7.49(m,4H),6.89(d,J=8.0Hz,2H),3.77(s,3H),2.23-2.16(m,2H),1.38-1.32(m,2H),0.90(t,J=8.0Hz,3H).
13C NMR(100MHz,CDCl3)δ191.9,185.2,159.6,135.2,130.0,128.9,128.4,125.9,125.8,114.0(overlap),90.4,55.2,40.8,16.8,13.7.
HRMS(EI):m/z:[M]+Calcd for C19H19NO3:309.1365,found 309.1362.[α]D20=-149.555(c=0.5,CHCl3).
HPLC测试条件:Daicel Chiralpak ODH色谱柱;正己烷/异丙醇=90/10,1.0mL/min,254nm;tr=7.54min(主峰),tr=8.04min(次峰).
实施例7
本实施例提供了一种式3f所示的手性α四取代的噁唑-4(5H)-酮的制备,反应方程如下所示:
在N2填充的手套箱内,在10mL史莱克管内加入Pd(OAc)2(6.6mg,0.03mmol,10mol%)、手性膦配体X1(33.0mg,0.036mmol,12mol%)和干燥的均三甲苯(3mL),室温下预搅拌1h。然后在手套箱内向封管内加入式1f所示的化合物(62.1mg,0.3mmol,1.0equiv)、式2a所示的化合物(91.4mg,0.45mmol,1.5equiv)和Rb2CO3(138.6mg,0.6mmol,2.0equiv)。N2保护下,反应体系在40℃油浴内搅拌反应48h,TLC确定原料反应完全。将溶剂旋干,粗产物用硅胶快速柱层析提纯(PE/EA展开剂)得到式3f所示的目标产物,产率为71%,ee值为87%。
对本实施例制备得到的产物进行测试表征,表征结果如下:
1H NMR(400MHz,CDCl3)δ8.39(d,J=8.0Hz,2H),8.07(s,1H),7.89-7.82(m,3H),7.76-7.71(m,2H),7.61-7.57(m,2H),7.49-7.48(m,2H),2.38-2.31(m,2H),1.46-1.39(m,2H),0.94(t,J=8.0Hz,3H).
13C NMR(100MHz,CDCl3)δ191.7,185.5,135.4,133.8,133.1,133.0,130.2,129.1,128.7,128.3,127.7,126.6,126.6,125.9,123.8,122.4,90.7,41.2,17.1,13.9.
HRMS(EI):m/z:[M]+Calcd for C22H19NO2:329.1416,found 329.1411.
[α]D20=-136.272(c=0.5,CHCl3).
HPLC测试条件:Daicel Chiralpak ODH色谱柱;正己烷/异丙醇=90/10,1.0mL/min,254nm;tr=7.28min(主峰),tr=8.16min(次峰).
实施例8
本实施例提供了一种式3g所示的手性α四取代的噁唑-4(5H)-酮的制备,反应方程如下所示:
在N2填充的手套箱内,在10mL史莱克管内加入Pd(OAc)2(6.6mg,0.03mmol,10mol%)、手性膦配体X1(33.0mg,0.036mmol,12mol%)和干燥的均三甲苯(3mL),室温下预搅拌1h。然后在手套箱内向封管内加入式1g所示的化合物(48.9mg,0.3mmol,1.0equiv)、式2a所示的化合物(91.4mg,0.45mmol,1.5equiv)和Rb2CO3(138.6mg,0.6mmol,2.0equiv)。N2保护下,反应体系在40℃油浴内搅拌反应48h,TLC确定原料反应完全。将溶剂旋干,粗产物用硅胶快速柱层析提纯(PE/EA展开剂)得到式3f所示的目标产物,产率为64%,ee值为89%。
对本实施例制备得到的产物进行测试表征,表征结果如下:
1H NMR(400MHz,CDCl3)δ8.31-8.28(m,2H),7.74-7.70(m,1H),7.58-7.54(m,2H),7.41-7.40(m,1H),7.35-7.33(m,1H),7.24-7.22(m,1H),2.30-2.15(m,2H),1.42-1.32(m,2H),0.92(t,J=8.0Hz,3H).
13C NMR(100MHz,CDCl3)δ191.3,185.4,137.0,135.3,130.1,129.0,126.7,125.8,124.8,121.6,89.6,40.4,16.8,13.7.
HRMS(EI):m/z:[M]+Calcd for C16H15NO2S:285.0823,found 285.0820.
[α]D20=-143.291(c=0.5,CHCl3).
HPLC测试条件:Daicel Chiralpak ODH色谱柱;正己烷/异丙醇=90/10,1.0mL/min,254nm;tr=7.51min(次峰),tr=8.16min(主峰).
实施例9
本实施例提供了一种式3h所示的手性α四取代的噁唑-4(5H)-酮的制备,反应方程如下所示:
在N2填充的手套箱内,在10mL史莱克管内加入Pd(OAc)2(6.6mg,0.03mmol,10mol%)、手性膦配体X1(43.5mg,0.045mmol,15mol%)和干燥的均三甲苯(3mL),室温下预搅拌1h。然后在手套箱内向封管内加入式1h所示的化合物(88.8mg,0.3mmol,1.0equiv)、式2a所示的化合物(91.4mg,0.45mmol,1.5equiv)和Rb2CO3(138.6mg,0.6mmol,2.0equiv)。N2保护下,反应体系在40℃油浴内搅拌反应48h,TLC确定原料反应完全。将溶剂旋干,粗产物用硅胶快速柱层析提纯(PE/EA展开剂)得到式3h所示的目标产物,产率为71%,ee值为85%。
对本实施例制备得到的产物进行测试表征,表征结果如下:
1H NMR(400MHz,CDCl3)δ8.37-8.35(m,2H),8.15-8.13(m,1H),7.79-7.79(m,1H),7.75-7.71(m,1H),7.61-7.54(m,4H),6.57-6.56(m,1H),2.36-2.20(m,2H),1.66(s,9H),1.43-1.34(m,2H),0.92(t,J=8.0Hz,3H).
13C NMR(100MHz,CDCl3)δ192.1,185.3,149.5,135.2,135.0,130.8,130.6,130.2,129.0,126.8,125.9,120.8,117.2,115.4,107.4,90.9,84.0,41.4,28.1,17.0,13.8.
HRMS(EI):m/z:[M]+Calcd for C25H26N2O4:418.1893,found 318.1362.
[α]D20=-135.592(c=0.5,CHCl3).
HPLC测试条件:Daicel Chiralpak OZ-3色谱柱;正己烷/异丙醇=90/10,1.0mL/min,254nm;tr=6.99min(次峰),tr=8.77min(主峰).
实施例10
本实施例提供了一种式3i所示的手性α四取代的噁唑-4(5H)-酮的制备,反应方程如下所示:
在N2填充的手套箱内,在10mL史莱克管内加入Pd(OAc)2(6.6mg,0.03mmol,10mol%)、手性膦配体X1(43.5mg,0.045mmol,15mol%)和干燥的均三甲苯(3mL),室温下预搅拌1h。然后在手套箱内向封管内加入式1a所示的化合物(47.1mg,0.3mmol,1.0equiv)、式2b所示的化合物(78.8mg,0.45mmol,1.5equiv)和Rb2CO3(138.6mg,0.6mmol,2.0equiv)。N2保护下,反应体系在40℃油浴内搅拌反应48h,TLC确定原料反应完全。将溶剂旋干,粗产物用硅胶快速柱层析提纯(PE/EA展开剂)得到式3i所示的目标产物,产率为83%,ee值为91%。
对本实施例制备得到的产物进行测试表征,表征结果如下:
1HNMR(400MHz,CDCl3)δ8.33(d,J=8.0Hz,2H),7.72(t,J=8.0Hz,1H),7.59-7.55(m,4H),7.40-7.34(m,3H),1.95(s,3H).
13C NMR(100MHz,CDCl3)δ191.9,185.1,137.0,135.3,130.1,129.0,128.7,128.6,125.8,124.5,87.4,24.9.
HRMS(EI):m/z:[M]+Calcd for C16H13NO2:251.0946,found 251.0941.
[α]D20=-105.316(c=0.5,CHCl3).
HPLC测试条件:Daicel Chiralpak ODH色谱柱;正己烷/异丙醇=90/10,1.0mL/min,254nm;tr=7.65min(主峰),tr=8.51min(次峰).
实施例11
本实施例提供了一种式3j所示的手性α四取代的噁唑-4(5H)-酮的制备,反应方程如下所示:
在N2填充的手套箱内,在10mL史莱克管内加入Pd(OAc)2(6.6mg,0.03mmol,10mol%)、手性膦配体X1(43.5mg,0.045mmol,15mol%)和干燥的均三甲苯(3mL),室温下预搅拌1h。然后在手套箱内向封管内加入式1a所示的化合物(47.1mg,0.3mmol,1.0equiv)、式2d所示的化合物(85.1mg,0.45mmol,1.5equiv)和Rb2CO3(138.6mg,0.6mmol,2.0equiv)。N2保护下,反应体系在40℃油浴内搅拌反应48h,TLC确定原料反应完全。将溶剂旋干,粗产物用硅胶快速柱层析提纯(PE/EA展开剂)得到式3j所示的目标产物,产率为75%,ee值为92%。
对本实施例制备得到的产物进行测试表征,表征结果如下:
1H NMR(400MHz,CDCl3)δ8.35-8.33(m,2H),7.72(t,J=8.0Hz,1H),7.62-7.56(m,4H),7.40-7.33(m,3H),2.31(q,J=8.0Hz,2H),0.95(t,J=8.0Hz,3H).
13C NMR(100MHz,CDCl3)δ191.5,185.4,136.2,135.2,130.0,129.0,128.6,128.4,125.7,124.5,90.8,32.3,7.8.
HRMS(EI):m/z:[M]+Calcd for C17H15NO2:265.1103,found 265.1098.
[α]D20=-149.531(c=0.5,CHCl3).
HPLC测试条件:Daicel Chiralpak ODH色谱柱;正己烷/异丙醇=95/5,0.5mL/min,254nm;tr=17.33min(主峰),tr=18.51min(次峰).
上述实施例2-11采用手性膦配体X1制备不同手性α四取代的噁唑-4(5H)-酮的收率及ee值如下表1所示:
表1
序号 | 产物 | 钯盐 | 溶剂 | 碱 | 收率 | ee值 |
实施例2 | 3a | 醋酸钯 | 均三甲苯 | 碳酸铷 | 76% | 93% |
实施例3 | 3b | 醋酸钯 | 均三甲苯 | 碳酸铷 | 86% | 91% |
实施例4 | 3c | 醋酸钯 | 均三甲苯 | 碳酸铷 | 82% | 89% |
实施例5 | 3d | 醋酸钯 | 均三甲苯 | 碳酸铷 | 85% | 92% |
实施例6 | 3e | 醋酸钯 | 均三甲苯 | 碳酸铷 | 81% | 91% |
实施例7 | 3f | 醋酸钯 | 均三甲苯 | 碳酸铷 | 71% | 87% |
实施例8 | 3g | 醋酸钯 | 均三甲苯 | 碳酸铷 | 64% | 89% |
实施例9 | 3h | 醋酸钯 | 均三甲苯 | 碳酸铷 | 71% | 85% |
实施例10 | 3i | 醋酸钯 | 均三甲苯 | 碳酸铷 | 83% | 91% |
实施例11 | 3j | 醋酸钯 | 均三甲苯 | 碳酸铷 | 75% | 92% |
实施例12-17
采用不同的手性膦配体X2~X7制备式3i所示的化合物,具体制备步骤参考实施例10,核磁测得收率和对映选择性(ee值),具体如下表2所示:
表2
序号 | 配体L* | 钯盐 | 溶剂 | 碱 | 收率 | ee值 |
实施例12 | X2 | 醋酸钯 | 均三甲苯 | 碳酸铷 | 77% | 89% |
实施例13 | X3 | 醋酸钯 | 均三甲苯 | 碳酸铷 | 66% | 68% |
实施例14 | X4 | 醋酸钯 | 均三甲苯 | 碳酸铷 | 75% | 78% |
实施例15 | X5 | 醋酸钯 | 均三甲苯 | 碳酸铷 | 78% | 59% |
实施例16 | X6 | 醋酸钯 | 均三甲苯 | 碳酸铷 | 49% | 53% |
实施例17 | X7 | 醋酸钯 | 均三甲苯 | 碳酸铷 | 18% | 57% |
对比例1-8
采用已知手性膦配体L1~L8制备式3i所示的化合物,具体制备步骤参考实施例10,手性膦配体L1~L8的结构如下所示:
核磁测得收率和对映选择性(ee值),具体如下表3所示:
表3
序号 | 配体L* | 钯盐 | 溶剂 | 碱 | 收率 | ee值 |
对比例1 | L1 | 醋酸钯 | 均三甲苯 | 碳酸铷 | 0% | - |
对比例2 | L2 | 醋酸钯 | 均三甲苯 | 碳酸铷 | 0% | - |
对比例3 | L3 | 醋酸钯 | 均三甲苯 | 碳酸铷 | 0% | - |
对比例4 | L4 | 醋酸钯 | 均三甲苯 | 碳酸铷 | 0% | - |
对比例5 | L5 | 醋酸钯 | 均三甲苯 | 碳酸铷 | 0% | - |
对比例6 | L6 | 醋酸钯 | 均三甲苯 | 碳酸铷 | 0% | - |
对比例7 | L7 | 醋酸钯 | 均三甲苯 | 碳酸铷 | 0% | - |
对比例8 | L8 | 醋酸钯 | 均三甲苯 | 碳酸铷 | 0% | - |
由上表1-3可知,本发明通过反应底物的选择,并在特定手性膦配体X1-X7及钯催化剂的作用下,可合成手性α四取代的噁唑-4(5H)-酮,其中采用手性膦配体X1、X2制备得到的产物,产率高且ee值高。而在上述合成体系中,采用手性膦配体L1-L8则无法制备得到手性α四取代的噁唑-4(5H)-酮。
以上所述实施例仅是为充分说明本发明而所举的较佳的施例,本发明的保护范围不限于此。本技术领域的技术人员在本发明基础上所作的等同替代或变换,均在本发明的保护范围之内。本发明的保护范围以权利要求书为准。
Claims (10)
1.一种手性α四取代的噁唑-4(5H)-酮的制备方法,其特征在于,在保护气氛下,将式(I)所示的化合物与式(II)所示的化合物在钯催化剂、手性膦配体、碱以及溶剂的存在下反应,得到式(III)所示的手性α四取代的噁唑-4(5H)-酮;
上述式(I)~式(III)的结构如下:
其中,A选自取代或未取代的苯基、取代或未取代的噻吩基、取代或未取代的萘基、取代或未取代的吲哚基中的一种;
R1选自取代或未取代的C1-6烷基、取代或未取代的苄基中的一种;
Ar1为取代或未取代的苯基;
取代或未取代表示该基团被一个或多个取代基取代或未被取代,所述取代基选自卤素、C1-6烷基、C1-6烷氧基、三氟甲基、酮羰基、芳基中的一种。
所述手性膦配体选自以下结构中的一种:
2.根据权利要求1所述的制备方法,其特征在于,A选自苯基、卤素取代的苯基、C1-6烷基取代的苯基、噻吩基、萘基、酮羰基取代的吲哚基中的一种,R1为C1-6烷基。
3.根据权利要求1所述的制备方法,其特征在于,先将钯催化剂与手性膦配体在溶剂中混合,形成催化剂[Pd]/L*溶液,然后将式(I)所示的化合物、式(II)所示的化合物及碱加入催化剂[Pd]/L*溶液中反应,得到所述手性α四取代的噁唑-4(5H)-酮。
4.根据权利要求1所述的制备方法,其特征在于,所述手性膦配体为式X1所示的化合物和/或式X2所示的化合物。
5.根据权利要求1所述的制备方法,其特征在于,所述钯催化剂选自醋酸钯、三氟乙酸钯、二氯二乙腈钯、氯化钯、金刚烷甲酸钯中的一种或多种。
6.根据权利要求1所述的制备方法,其特征在于,所述碱选自碳酸钠、碳酸钾、碳酸铯、碳酸铷、磷酸钾中的一种或多种。
7.根据权利要求1所述的制备方法,其特征在于,所述溶剂选自二氯甲烷、2-甲基四氢呋喃、四氢呋喃、三氟甲苯、甲苯、均三甲苯、氯苯、乙酸乙酯、正己烷、甲基叔丁基醚、苯甲醚、异丙醚、正丁醚、乙醚中的一种或多种。
8.根据权利要求1所述的制备方法,其特征在于,所述钯催化剂为醋酸钯,所述碱为碳酸铷,所述溶剂为均三甲苯。
9.根据权利要求1所述的制备方法,其特征在于,式(I)所示的化合物与式(II)所示的化合物、钯催化剂、手性膦配体、碱的投料摩尔比为1:1-2:0.025-0.1:0.03-0.2:1-2.5。
10.根据权利要求1所述的制备方法,其特征在于,所述反应的反应温度为20-100℃,反应时间为6-60h。
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