CN113999133A - Synthesis method of unsaturated carbonyl functionalized alpha-hydroxyamide - Google Patents
Synthesis method of unsaturated carbonyl functionalized alpha-hydroxyamide Download PDFInfo
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- CN113999133A CN113999133A CN202111426503.1A CN202111426503A CN113999133A CN 113999133 A CN113999133 A CN 113999133A CN 202111426503 A CN202111426503 A CN 202111426503A CN 113999133 A CN113999133 A CN 113999133A
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 title description 4
- 238000001308 synthesis method Methods 0.000 title description 3
- 238000000034 method Methods 0.000 claims abstract description 23
- -1 alpha-ketoamide compound Chemical class 0.000 claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims description 25
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 21
- 239000003054 catalyst Substances 0.000 claims description 18
- 125000001424 substituent group Chemical group 0.000 claims description 17
- 239000002904 solvent Substances 0.000 claims description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 239000012046 mixed solvent Substances 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- 150000007530 organic bases 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
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 claims description 3
- 239000012295 chemical reaction liquid Substances 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- 238000010898 silica gel chromatography Methods 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000005561 phenanthryl group Chemical group 0.000 claims description 2
- 238000012805 post-processing Methods 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 125000001725 pyrenyl group Chemical group 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 229910044991 metal oxide Inorganic materials 0.000 claims 3
- 150000004706 metal oxides Chemical class 0.000 claims 3
- 238000005575 aldol reaction Methods 0.000 abstract description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 13
- 239000001211 (E)-4-phenylbut-3-en-2-one Substances 0.000 description 7
- BWHOZHOGCMHOBV-UHFFFAOYSA-N Benzalacetone Natural products CC(=O)C=CC1=CC=CC=C1 BWHOZHOGCMHOBV-UHFFFAOYSA-N 0.000 description 7
- BWHOZHOGCMHOBV-BQYQJAHWSA-N trans-benzylideneacetone Chemical compound CC(=O)\C=C\C1=CC=CC=C1 BWHOZHOGCMHOBV-BQYQJAHWSA-N 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- FGFUBBNNYLNVLJ-UHFFFAOYSA-N indolone Natural products C1=CC=C2C(=O)C=NC2=C1 FGFUBBNNYLNVLJ-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- QMGHHBHPDDAGGO-IIWOMYBWSA-N (2S,4R)-1-[(2S)-2-[[2-[3-[4-[3-[4-[[5-bromo-4-[3-[cyclobutanecarbonyl(methyl)amino]propylamino]pyrimidin-2-yl]amino]phenoxy]propoxy]butoxy]propoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide Chemical compound CN(CCCNC1=NC(NC2=CC=C(OCCCOCCCCOCCCOCC(=O)N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)NCC3=CC=C(C=C3)C3=C(C)N=CS3)C(C)(C)C)C=C2)=NC=C1Br)C(=O)C1CCC1 QMGHHBHPDDAGGO-IIWOMYBWSA-N 0.000 description 1
- IZGDXVLRMHXOJV-SFHVURJKSA-N (3s)-4-[2-[2-(4-fluoro-3-methylphenyl)-4-methyl-6-propan-2-ylphenyl]ethyl-hydroxyphosphoryl]-3-hydroxybutanoic acid Chemical compound CC(C)C1=CC(C)=CC(C=2C=C(C)C(F)=CC=2)=C1CCP(O)(=O)C[C@@H](O)CC(O)=O IZGDXVLRMHXOJV-SFHVURJKSA-N 0.000 description 1
- WHQUHTXULUACFD-KRWDZBQOSA-N (3s)-4-[[2-(4-fluoro-3-methylphenyl)-4-methyl-6-propan-2-ylphenyl]methoxy-hydroxyphosphoryl]-3-hydroxybutanoic acid Chemical compound CC(C)C1=CC(C)=CC(C=2C=C(C)C(F)=CC=2)=C1COP(O)(=O)C[C@@H](O)CC(O)=O WHQUHTXULUACFD-KRWDZBQOSA-N 0.000 description 1
- MNIPVWXWSPXERA-IDNZQHFXSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecanoyloxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OC(=O)CCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 MNIPVWXWSPXERA-IDNZQHFXSA-N 0.000 description 1
- BOOYHBPHFVNWNH-OAHLLOKOSA-N 1-tert-butyl-6-[[(1R)-1-(4-chlorophenyl)ethyl]amino]-5-[(4-fluorophenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-one Chemical compound C[C@H](C1=CC=C(C=C1)Cl)NC2=NC3=C(C=NN3C(C)(C)C)C(=O)N2CC4=CC=C(C=C4)F BOOYHBPHFVNWNH-OAHLLOKOSA-N 0.000 description 1
- PSWDQTMAUUQILQ-UHFFFAOYSA-N 2-[(6-methoxy-4-methylquinazolin-2-yl)amino]-5,6-dimethyl-1h-pyrimidin-4-one Chemical compound N1=C(C)C2=CC(OC)=CC=C2N=C1NC1=NC(=O)C(C)=C(C)N1 PSWDQTMAUUQILQ-UHFFFAOYSA-N 0.000 description 1
- 229940126650 Compound 3f Drugs 0.000 description 1
- KGPGFQWBCSZGEL-ZDUSSCGKSA-N GSK690693 Chemical compound C=12N(CC)C(C=3C(=NON=3)N)=NC2=C(C#CC(C)(C)O)N=CC=1OC[C@H]1CCCNC1 KGPGFQWBCSZGEL-ZDUSSCGKSA-N 0.000 description 1
- 241000334160 Isatis Species 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940125796 compound 3d Drugs 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000012973 diazabicyclooctane Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- QNLOWBMKUIXCOW-UHFFFAOYSA-N indol-2-one Chemical compound C1=CC=CC2=NC(=O)C=C21 QNLOWBMKUIXCOW-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- MUTCAPXLKRYEPR-ITWZMISCSA-N methyl (e,3r,5s)-7-[4-bromo-2,3-bis(4-fluorophenyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyhept-6-enoate Chemical compound COC(=O)C[C@H](O)C[C@H](O)\C=C\N1C(C(C)C)=C(Br)C(C=2C=CC(F)=CC=2)=C1C1=CC=C(F)C=C1 MUTCAPXLKRYEPR-ITWZMISCSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- PEECTLLHENGOKU-UHFFFAOYSA-N n,n-dimethylpyridin-4-amine Chemical compound CN(C)C1=CC=NC=C1.CN(C)C1=CC=NC=C1 PEECTLLHENGOKU-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 150000005623 oxindoles Chemical class 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B41/00—Formation or introduction of functional groups containing oxygen
- C07B41/02—Formation or introduction of functional groups containing oxygen of hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a novel method for preparing an alpha-hydroxy amide compound by Aldol reaction of an alpha-ketoamide compound with an open-chain structure and a butyl-3-alkene-2-ketone compound.
Description
Technical Field
The application belongs to the technical field of organic synthesis methodology, and particularly relates to a synthesis method of unsaturated carbonyl functionalized alpha-hydroxyamide.
Background
The multi-functionalized alpha-hydroxy amide compound is a main skeleton and an important synthesis intermediate of a plurality of drug molecules, and has important research value in organic synthesis and medical intermediate synthesis. Tinting Yan et al reported the Aldol reaction of a cyclic indolone compound with (E) -4-phenyl-but-3-en-2-one under the catalysis of an amino acid such as Arginine (simple Creation of 3-substistuted-3-Hydroxy-2-oxides by aromatic-Catalyzed aldols of α, β -unreacted Ketone with Isatis, tinting Yan et al, Molecules 2013,18(12),14505-14518), Arginine activation of (E) -4-phenyl-but-3-en-2-one as an enamine intermediate followed by reaction with a receptor indolone compound, however this method is only limited to a specific cyclic indolone compound and the reaction requires 48h to complete and is inefficient. Mariana Gavendova et al reported the Aldol reaction of indolone with acetone (Novel beta-amino Amide organic catalysts for the Synthesis of pharmaceutical Relevant Oxindoles, Mariana Gavendova et al, chemistry select 4(28),8246-8254), which requires a specific chiral catalyst and is still only suitable for cyclic diketone substrates of specific structure. The inventor finds that the Aldol reaction of the alpha-ketoamide compound with the open-chain structure and the (E) -4-phenyl-but-3-en-2-one is not reported in the prior art through extensive literature research, so that the development of a catalyst system which is low in raw material price, simple in reaction system and single and is suitable for industrial production has important significance for the synthesis and application of the compound.
The inventor researches and discovers that the Aldol reaction of the alpha-ketoamide compound with the open-chain structure and (E) -4-phenyl-but-3-en-2-one can be efficiently realized under the condition of using common alkali potassium hydroxide as a catalyst and using an aqueous phase system, the unsaturated alpha-hydroxy amide compound can be obtained with high yield, the reaction condition is mild, the time is short, the reaction system is simple, and the method is suitable for industrial production.
Disclosure of Invention
The invention aims to provide a novel method for preparing an alpha-hydroxy amide compound by Aldol reaction of an alpha-ketoamide compound with an open-chain structure and a butyl-3-alkene-2-ketone compound.
The invention provides a method for synthesizing unsaturated carbonyl functionalized alpha-hydroxyamide, which comprises the following steps:
adding an open-chain alpha-ketoamide compound shown in formula 1, a butyl-3-alkene-2-ketone compound shown in formula 2, a catalyst and a solvent into a reactor in sequence, stirring at room temperature for reaction, and performing post-treatment after the reaction is completed to obtain an alpha-hydroxy amide compound shown in formula 3, wherein the reaction formula is as follows:
in the above reaction formula, R1,R2,R3Each represents one or more substituents on the attached phenyl ring, each substituent being independently selected from hydrogen, halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C6-20Aryl radical, C1-6Haloalkyl, C2-20A heteroaryl group; and/or two adjacent substituents are linked to each other to form a five-to seven-membered ring structure with or without heteroatoms.
Preferably, R1,R2,R3Each represents one or more substituents on the attached phenyl ring, each substituent being independently selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, methoxy, ethoxy, tert-butoxy, phenyl, naphthyl, anthryl, phenanthryl, pyrenyl, fluorenyl, trifluoromethyl, furyl, thienyl, pyridyl, imidazolyl, pyrrolyl; and/or two adjacent substituents are linked to each other to form a five-to seven-membered ring structure free of heteroatoms.
Further preferably, R1,R2Each represents one or more substituents on the attached phenyl ring, each substituent being independently selected from hydrogen, fluoro, chloro, bromo, iodo, methyl, ethyl, methoxy, ethoxy; r3Selected from hydrogen.
The method according to the present invention, wherein the catalyst is an organic base and/or an inorganic base; the organic base is selected from one or more of tetramethylguanidine, potassium tert-butoxide and DBU; the inorganic base is one or more selected from potassium carbonate, potassium hydroxide and sodium hydroxide. Preferably, the catalyst is potassium hydroxide.
The method according to the present invention, wherein the solvent is selected from any one of methanol, tetrahydrofuran, dioxane and acetonitrile, or a mixed solvent of the above solvent and water. Preferably, the solvent is selected from a mixed solvent of dioxane and water; still more preferably, the volume ratio of dioxane to water is 1:1.
According to the method, the feeding molar ratio of the open-chain alpha-ketoamide compound shown in the formula 1, the butyl-3-alkene-2-ketone compound shown in the formula 2 and the catalyst is 1 (1-3) to (0.1-0.3); preferably, the feeding molar ratio of the open-chain alpha-ketoamide compound shown in the formula 1, the butyl-3-alkene-2-ketone compound shown in the formula 2 to the catalyst is 1 (1.5-2) to 0.2.
The method according to the present invention, wherein the post-processing operation is as follows: after the reaction is completed, extracting the reaction liquid by dichloromethane, drying, concentrating, and separating by silica gel column chromatography to obtain the alpha-hydroxy amide compound shown in the formula 3.
The method of the invention has the following beneficial effects:
the invention reports a method for preparing an alpha-hydroxy amide compound by an Aldol reaction of an open-chain alpha-ketoamide compound and (E) -4-phenyl-but-3-en-2-one for the first time, the unsaturated alpha-hydroxy amide compound is obtained with high yield under the condition of a water phase system by taking common alkali potassium hydroxide as a catalyst, the reaction condition is mild, the time is short, the reaction system is simple, and the method is suitable for industrial production.
Detailed Description
The present invention will be described in further detail with reference to specific examples. In the following, unless otherwise specified, all methods involved are conventional in the art, and the reagents used are either purchased commercially from conventional sources in the art and without further purification treatment, and/or prepared according to synthetic methods known in the art.
Examples 1-19 optimization of reaction conditions
The open-chain alpha-benzoyl-N-phenylamide shown in the formula 1 and the (E) -4-phenyl-but-3-en-2-one shown in the formula 2 are used as templates, the influence on the reaction time and the yield of a target product under the conditions of different solvents, catalysts and feeding ratios is researched, and the reaction formula is as follows:
using example 19 as an example, a typical experimental run for examples 1-19 is as follows:
adding open-chain alpha-benzoyl-N-phenylamide (0.1mmol) shown in formula 1a, (E) -4-phenyl-but-3-en-2-one (0.15mmol) shown in formula 2a, KOH (0.02mmol), 1, 4-dioxane/water (volume ratio v/v ═ 1:1,1mL) into a reactor in sequence, stirring at room temperature for reaction for 1h, detecting the reaction completion by TLC, adding dichloromethane into the reaction liquid for extraction, drying, concentrating in vacuum to obtain a residue, and separating the residue by silica gel column chromatography (eluting solvent N-hexane/ethyl acetate mixed solvent) to obtain the alpha-hydroxyamide compound shown in formula 3 a. The yield was 94%.1H NMR(400MHz,Chloroform-d)δ8.73(s,1H),7.80–7.65(m,3H),7.59(t,J＝8.0Hz,4H),7.49–7.39(m,5H),7.39–7.32(m,3H),7.12(t,J＝7.5Hz,1H),6.80(d,J＝16.3Hz,1H),6.04(s,1H),4.02(d,J＝17.4Hz,1H),3.22(d,J＝17.3Hz,1H)。
Table 1:
wherein each English abbreviation represents the following meanings:
DABCO is triethylene diamine;
DBU is 1, 8-diazabicyclo [5.4.0] undec-7-ene;
Et3n: triethylamine;
TMG: tetramethyl guanidine;
DMAP 4-dimethylaminopyridine;
KTB is potassium tert-butoxide.
As can be seen from table 1, the optimal reaction conditions for this application are sodium hydroxide as catalyst, 1, 4-dioxane/water volume ratio of 1:1 as solvent, and formula 1a is selected for raw material cost saving: formula 2 a: the optimal ratio of the molar ratio of the catalyst is 1:1.5:0.2, and the yield of the target product can be up to 94% after 1 hour of reaction.
Based on the optimal reaction conditions (example 19), the inventors further explored the applicability of the optimal reaction conditions to the substrate substituent, that is, only the raw material species are replaced, the rest of the process operations and parameters are the same as those in example 19, and the yield and structural characterization data of a series of α -hydroxy amide compounds are as follows:
compound 3b:
1H NMR(400MHz,Chloroform-d)δ8.63(s,1H),7.79–7.65(m,3H),7.58(d,J＝6.3Hz,2H),7.43(q,J＝9.7,7.3Hz,7H),7.34(t,J＝7.0Hz,1H),6.92–6.70(m,3H),5.99(s,1H),3.99(d,J＝17.3Hz,1H),3.79(s,3H),3.20(d,J＝17.3Hz,1H)。
compound 3c:
1H NMR(500MHz,Chloroform-d)δ8.64(s,1H),7.85(d,J＝8.1Hz,1H),7.73(d,J＝7.6Hz,2H),7.66(d,J＝16.2Hz,1H),7.54(d,J＝7.7Hz,2H),7.42–7.36(m,5H),7.31(t,J＝7.3Hz,1H),7.14(dd,J＝14.3,7.2Hz,2H),7.01(t,J＝7.4Hz,1H),6.75(d,J＝16.2Hz,1H),6.03(s,1H),3.99(d,J＝17.3Hz,1H),3.17(d,J＝17.3Hz,1H),2.20(s,3H)。
compound 3d:
1H NMR(500MHz,Chloroform-d)δ8.64(s,1H),7.73–7.62(m,3H),7.53(d,J＝7.6Hz,2H),7.38(dd,J＝14.6,7.4Hz,6H),7.29(dd,J＝14.3,7.4Hz,2H),7.15(t,J＝7.8Hz,1H),6.88(d,J＝7.5Hz,1H),6.74(d,J＝16.2Hz,1H),5.97(s,1H),3.96(d,J＝17.3Hz,1H),3.16(d,J＝17.3Hz,1H),2.29(s,3H)。
compound 3e:
1H NMR(500MHz,Chloroform-d)δ8.58(s,1H),7.74–7.32(m,12H),7.29(t,J＝7.3Hz,1H),7.21(d,J＝6.9Hz,1H),7.02(d,J＝8.1Hz,1H),6.73(s,1H),5.95(s,1H),3.95(d,J＝17.3Hz,1H),3.16(d,J＝17.3Hz,1H),2.20(s,3H),2.18(s,3H)。
compound 3f:
1H NMR(400MHz,Chloroform-d)δ8.71(s,1H),7.75–7.65(m,3H),7.61–7.54(m,2H),7.49–7.38(m,9H),7.34(t,J＝7.2Hz,1H),6.78(d,J＝16.2Hz,1H),6.00(s,1H),3.98(d,J＝17.4Hz,1H),3.19(d,J＝17.4Hz,1H)。
compound 3g:
1H NMR(400MHz,Chloroform-d)δ8.72(s,1H),7.77–7.66(m,3H),7.65–7.56(m,4H),7.43(dd,J＝13.1,6.6Hz,5H),7.35(d,J＝8.5Hz,3H),6.79(d,J＝16.2Hz,1H),6.02(s,1H),3.99(d,J＝17.3Hz,1H),3.20(d,J＝17.4Hz,1H)。
compound 3h:
1H NMR(500MHz,Chloroform-d)δ8.76(s,1H),8.61(s,1H),8.32(s,1H),8.11(d,J＝9.0Hz,1H),7.73–7.63(m,3H),7.57–7.52(m,2H),7.40(dd,J＝10.4,7.8Hz,5H),7.32(t,J＝7.3Hz,1H),7.22(dd,J＝8.2,4.7Hz,1H),6.75(d,J＝16.2Hz,1H),6.01(s,1H),3.96(d,J＝17.4Hz,1H),3.18(d,J＝17.4Hz,1H)。
compound 3i:
1H NMR(500MHz,Chloroform-d)δ8.67(s,1H),7.76–7.61(m,3H),7.53(dd,J＝14.1,7.3Hz,4H),7.40(d,J＝6.9Hz,3H),7.28(t,J＝7.7Hz,2H),7.12–7.00(m,3H),6.74(d,J＝16.2Hz,1H),6.02(s,1H),3.91(d,J＝17.2Hz,1H),3.15(d,J＝17.2Hz,1H)。
compound 3j:
1H NMR(500MHz,Chloroform-d)δ8.67(s,1H),7.68–7.61(m,3H),7.52(dd,J＝15.2,7.7Hz,4H),7.40(d,J＝7.2Hz,3H),7.34(d,J＝8.5Hz,2H),7.28(t,J＝7.8Hz,2H),7.07(t,J＝7.3Hz,1H),6.74(d,J＝16.2Hz,1H),6.03(s,1H),3.90(d,J＝17.3Hz,1H),3.15(d,J＝17.3Hz,1H)。
compound 3k:
1H NMR(500MHz,Chloroform-d)δ8.66(s,1H),7.63(s,1H),7.60(d,J＝8.4Hz,2H),7.56–7.47(m,6H),7.41(t,J＝6.6Hz,3H),7.28(t,J＝7.7Hz,2H),7.08(t,J＝7.3Hz,1H),6.74(d,J＝16.2Hz,1H),6.02(s,1H),3.89(d,J＝17.3Hz,1H),3.15(d,J＝17.3Hz,1H)。
compound 3l:
1H NMR(400MHz,Chloroform-d)δ8.71(s,1H),7.69(d,J＝16.2Hz,1H),7.63(d,J＝8.0Hz,2H),7.57(t,J＝7.1Hz,4H),7.44(d,J＝6.1Hz,3H),7.32(d,J＝7.9Hz,2H),7.23(d,J＝7.9Hz,2H),7.10(t,J＝7.3Hz,1H),6.78(d,J＝16.2Hz,1H),5.98(s,1H),3.98(d,J＝17.3Hz,1H),3.20(d,J＝17.3Hz,1H),2.37(s,3H)。
compound 3m:
1H NMR(500MHz,Chloroform-d)δ8.68(s,1H),7.75(s,1H),7.66(d,J＝16.2Hz,1H),7.59(d,J＝7.0Hz,1H),7.53(dd,J＝13.5,7.7Hz,4H),7.41(d,J＝7.0Hz,3H),7.29(t,J＝7.4Hz,4H),7.08(t,J＝7.3Hz,1H),6.74(d,J＝16.2Hz,1H),6.05(s,1H),3.93(d,J＝17.3Hz,1H),3.14(d,J＝17.3Hz,1H)。
the embodiments described above are only preferred embodiments of the invention and are not exhaustive of the possible implementations of the invention. Any obvious modifications to the above would be obvious to those of ordinary skill in the art, but would not bring the invention so modified beyond the spirit and scope of the present invention.
Claims (9)
1. A method for synthesizing an unsaturated carbonyl-functionalized α -hydroxyamide comprising the steps of:
adding an open-chain alpha-ketoamide compound shown in formula 1, a butyl-3-alkene-2-ketone compound shown in formula 2, a catalyst and a solvent into a reactor in sequence, stirring at room temperature for reaction, and performing post-treatment after the reaction is completed to obtain an alpha-hydroxy amide compound shown in formula 3, wherein the reaction formula is as follows:
in the above reaction formula, R1,R2,R3Each represents one or more substituents on the attached phenyl ring, each substituent being independently selected from hydrogen, halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C6-20Aryl radical, C1-6Haloalkyl, C2-20A heteroaryl group; and/or two adjacent substituents are linked to each other to form a five-to seven-membered ring structure with or without heteroatoms;
wherein, the catalyst is organic base and/or inorganic base; the organic base is selected from one or more of tetramethylguanidine, potassium tert-butoxide and DBU; the inorganic base is one or more selected from potassium carbonate, potassium hydroxide and sodium hydroxide;
the solvent is selected from any one of methanol, tetrahydrofuran, dioxane and acetonitrile, or a mixed solvent of the solvent and water.
2. The method of claim 1, wherein the step of removing the metal oxide layer comprises removing the metal oxide layer from the metal oxide layer，R1,R2,R3Each represents one or more substituents on the attached phenyl ring, each substituent being independently selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, methoxy, ethoxy, tert-butoxy, phenyl, naphthyl, anthryl, phenanthryl, pyrenyl, fluorenyl, trifluoromethyl, furyl, thienyl, pyridyl, imidazolyl, pyrrolyl; and/or two adjacent substituents are linked to each other to form a five-to seven-membered ring structure free of heteroatoms.
3. The method of claim 1 or 2, wherein R is1,R2Each represents one or more substituents on the attached phenyl ring, each substituent being independently selected from hydrogen, fluoro, chloro, bromo, iodo, methyl, ethyl, methoxy, ethoxy; r3Selected from hydrogen.
4. The process of claim 1 or 2, wherein the catalyst is potassium hydroxide.
5. The method according to claim 1 or 2, wherein the solvent is selected from a mixed solvent of dioxane and water.
6. The method of claim 5, wherein the volume ratio of dioxane to water is 1:1.
7. The method according to claim 1 or 2, wherein the molar ratio of the open-chain α -ketoamide compound represented by formula 1 to the but-3-en-2-one compound represented by formula 2 to the catalyst is 1 (1-3) to (0.1-0.3).
8. The method according to claim 7, wherein the molar ratio of the open-chain α -ketoamide compound represented by formula 1 to the but-3-en-2-one compound represented by formula 2 to the catalyst is 1 (1.5-2) to 0.2.
9. A method according to claim 1 or 2, characterized in that the post-processing operation is as follows: after the reaction is completed, extracting the reaction liquid by dichloromethane, drying, concentrating, and separating by silica gel column chromatography to obtain the alpha-hydroxy amide compound shown in the formula 3.
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