CN113999132B - 一种α-羟基β-硝基酰胺类化合物的合成方法 - Google Patents
一种α-羟基β-硝基酰胺类化合物的合成方法 Download PDFInfo
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- 238000001308 synthesis method Methods 0.000 title claims description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 42
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 17
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 claims abstract description 16
- 229930064664 L-arginine Natural products 0.000 claims abstract description 16
- 235000014852 L-arginine Nutrition 0.000 claims abstract description 16
- -1 alpha-ketoamide compounds Chemical class 0.000 claims abstract description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000002904 solvent Substances 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 238000010189 synthetic method Methods 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 239000012074 organic phase Substances 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 238000010898 silica gel chromatography Methods 0.000 claims description 3
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims 1
- 238000006842 Henry reaction Methods 0.000 abstract description 11
- 239000000758 substrate Substances 0.000 abstract description 9
- 239000003054 catalyst Substances 0.000 abstract description 8
- 235000001014 amino acid Nutrition 0.000 abstract description 4
- 150000001413 amino acids Chemical class 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 239000007810 chemical reaction solvent Substances 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 84
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 21
- 238000005160 1H NMR spectroscopy Methods 0.000 description 21
- 239000007787 solid Substances 0.000 description 21
- 238000003786 synthesis reaction Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- 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 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 125000001072 heteroaryl group Chemical group 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 3
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- 238000004519 manufacturing process Methods 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 description 2
- 125000006651 (C3-C20) cycloalkyl group Chemical group 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- 235000021513 Cinchona Nutrition 0.000 description 2
- 241000157855 Cinchona Species 0.000 description 2
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 2
- 229930013930 alkaloid Natural products 0.000 description 2
- 150000003797 alkaloid derivatives Chemical class 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
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- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 238000006053 organic reaction Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 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
- RTTUBUXMNUJHRR-DXRVJIQQSA-N (3s)-4-[[(e)-2-[1-(4-fluorophenyl)-3-propan-2-ylindol-2-yl]ethenyl]-hydroxyphosphoryl]-3-hydroxybutanoic acid Chemical compound C12=CC=CC=C2C(C(C)C)=C(\C=C\P(O)(=O)C[C@@H](O)CC(O)=O)N1C1=CC=C(F)C=C1 RTTUBUXMNUJHRR-DXRVJIQQSA-N 0.000 description 1
- AOSODOHQJJPEAM-VUVZNRFTSA-N (3s)-4-[[(e)-2-[3'-(4-fluorophenyl)spiro[cyclopentane-1,1'-indene]-2'-yl]ethenyl]-hydroxyphosphoryl]-3-hydroxybutanoic acid Chemical compound OC(=O)C[C@H](O)CP(O)(=O)\C=C\C1=C(C=2C=CC(F)=CC=2)C2=CC=CC=C2C11CCCC1 AOSODOHQJJPEAM-VUVZNRFTSA-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
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 1
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-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
- JWHYSEDOYMYMNM-QGZVFWFLSA-N 2-[4-[(2r)-2-ethoxy-3-[4-(trifluoromethyl)phenoxy]propyl]sulfanyl-2-methylphenoxy]acetic acid Chemical compound C([C@@H](OCC)CSC=1C=C(C)C(OCC(O)=O)=CC=1)OC1=CC=C(C(F)(F)F)C=C1 JWHYSEDOYMYMNM-QGZVFWFLSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- 229940126650 Compound 3f Drugs 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 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
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- HFIVLLBFACNAFN-UHFFFAOYSA-N [1-amino-2-[2-(4-methoxyphenyl)ethylamino]ethyl]phosphonic acid Chemical compound COc1ccc(CCNCC(N)P(O)(O)=O)cc1 HFIVLLBFACNAFN-UHFFFAOYSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 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 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
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
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- 230000003197 catalytic effect Effects 0.000 description 1
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- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 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
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000004971 nitroalkyl group Chemical group 0.000 description 1
- 238000012803 optimization experiment Methods 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- SERHXTVXHNVDKA-UHFFFAOYSA-N pantolactone Chemical compound CC1(C)COC(=O)C1O SERHXTVXHNVDKA-UHFFFAOYSA-N 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 125000001725 pyrenyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000004799 α-ketoamides Chemical class 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种水相中L‑精氨酸催化的Henry反应以制备α‑羟基β‑硝基酰胺类化合物的新方法。该方法以α‑酮酰胺类化合物和硝基甲烷为反应原料,天然氨基酸作为催化剂,水为反应溶剂,在室温条件下反应制备获得α‑羟基β‑硝基酰胺类化合物。反应条件温和简单、经济便宜、具有宽泛的反应底物适用范围和优异的目标产物收率。
Description
技术领域
本申请属于有机合成技术领域,具体涉及一种α-羟基β-硝基酰胺类化合物的合成方法。
背景技术
羰基化合物和硝基烷烃在碱的作用下发生的硝醇缩合被称为Henry反应,其是有机合成反应中一类非常重要的构建C-C键的有机反应,被广泛地应用于医药中间体和天然产物的合成,产物α-羟基β-硝基酰胺类化合物是重要有的有机合成中间体。传统的Henry反应在碱催化下进行,不对称催化Henry反应则需要更为复杂的反应条件,一般而言需要在有机溶剂条件下,以金属/配体络合物、手性脲或硫脲等为催化剂,实现产物的构型控制。以水为溶剂的有机反应具有显著的原子经济性并降低生产成本,因此开发水相中的Henry反应有很好的应用价值,在工业生产中有很好的应用前景。Christian Wolf等报道了一种以α-酮酰胺为原料制备α-羟基β-硝基酰胺类化合物的合成方法(Angew.Chem.Int.Ed.2011,50,12249-12252),但其依赖金属结合配体催化,催化体系相对复杂,反应在有机溶剂中进行,且底物兼容性很差,只适用于11个底物,不利于工业化生产。因此如何对Henry反应的反应条件进行优化,以开发简单可行、经济便宜、底物适用范围广的合成策略,进而制备获得所需要的α-羟基β-硝基酰胺类化合物仍然是本领域研究人员亟待解决的技术问题。天然氨基酸来源广泛,价格低廉,同时也具有环境友好的优点,但是其应用于催化Henry反应的研究则未见报道。
发明内容
本发明的目的在于克服现有技术的缺陷,提供一种水相中L-精氨酸催化的Henry反应以制备α-羟基β-硝基酰胺类化合物的新方法。该方法以α-酮酰胺类化合物和硝基甲烷为反应原料,天然氨基酸作为催化剂,水为反应溶剂,在室温条件下反应制备获得α-羟基β-硝基酰胺类化合物。反应条件温和简单、经济便宜、具有宽泛的反应底物适用范围和优异的目标产物收率。
根据本发明提供的一种α-羟基β-硝基酰胺类化合物的合成方法,包括如下步骤:
向反应器中加入式1所示的α-酮酰胺类化合物、式2所示的硝基甲烷、L-精氨酸和溶剂水,随后将反应器在室温下搅拌反应,反应完全后经纯化处理得到式3所示的α-羟基β-硝基酰胺类化合物,反应式如下:
上述反应式中,R1,R2彼此独立地选自取代或未取代的C1-20烷基、取代或未取代的C6-20芳基、取代或未取代的C3-20环烷基、取代或未取代的C2-20杂芳基。
优选地,R1,R2彼此独立地选自取代或未取代的C1-6烷基、取代或未取代的C6-12芳基、取代或未取代的C3-12环烷基、取代或未取代的C2-12杂芳基。
在本发明的任意部分中,作为所述C1-20烷基和/或C1-6烷基的例子,可以选自例如甲基、乙基、正丙基、异丙基、丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、正庚基、正辛基、正壬基、正癸基、十一烷基、十二烷基等;优选为甲基、乙基、正丙基、叔丁基。
在本发明的任意部分中,作为所述C6-20芳基和/或C6-12芳基的例子,可以选自例如苯基、萘基、蒽基、菲基、芘基、芴基等;优选为苯基或萘基。
在本发明的任意部分中,作为所述C3-20环烷基和/或C3-12环烷基的例子,可以选自例如环丙基、环丁基、环戊基、环己基、环庚基、金刚烷基等;优选为环丙基、环己基、金刚烷基。
在本发明的任意部分中,作为所述C2-20杂芳基和/或C2-12杂芳基的例子,可以选自例如呋喃基、吡啶基、咪唑基、吲哚基、咔唑基、吡咯基、噻吩基、嘧啶基、恶唑基、异恶唑基、噻唑基、异噻唑基等;优选为呋喃基、噻吩基、吡啶基、咪唑基、吡咯基。
在本发明的任意部分中,所述取代或未取代的中的取代基选自卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6酰基、-NO2、-CN;优选为氟、氯、溴、碘、甲基、乙基、叔丁基、甲氧基、乙氧基、乙酰基、-NO2、-CN;最优选为氟、氯、溴、碘、甲基、甲氧基。
根据本发明前述的方法,式1化合物选自如下化合物:
根据本发明前述的方法,式1所示的α-酮酰胺类化合物、式2所示的硝基甲烷、L-精氨酸的投料摩尔比为1:(5~40):(0.1~0.3);优选地,式1所示的α-酮酰胺类化合物、式2所示的硝基甲烷、L-精氨酸的投料摩尔比为1:20:0.2。
根据本发明前述的方法,其中所述搅拌反应的反应时间为4~48h,优选为6~24h,最优选为6h。
根据本发明前述的方法,其中所述纯化处理具体操作如下:
反应完全后向反应液中加入二氯甲烷萃取,合并有机相,干燥、浓缩、用乙酸乙酯和正己烷作为洗脱溶剂经硅胶柱层析分离得到式3所示的α-羟基β-硝基酰胺类化合物。
本发明的方法具有如下有益的效果:
1)本发明首次报道了L-精氨酸催化α-酮酰胺类化合物与硝基甲烷的Henry反应制备α-羟基β-硝基酰胺类化合物的方法,丰富了α-羟基β-硝基酰胺类化合物的合成途径。
2)本发明的合成策略使用水为溶剂具有良好的原子经济性,L-精氨酸为催化剂价格便宜、来源广泛、环境友好,以及本发明的合成策略在室温下进行Henry反应,反应条件温和简单、经济高效,具有宽泛的反应底物适应范围,且目标产物产率最高可达98%。
具体实施方式
以下结合具体实施例,对本发明作进一步地详述。在下文中,如无特殊说明,所涉及的方法均为本领域的常规方法,所使用的试剂均由本领域常规商业途径购买获得且未经进一步纯化处理,和/或根据本领域已知合成方法制备获得。
实施例1-14反应条件优化试验
以式1a所示的α-酮酰胺类化合物为反应底物,与硝基甲烷反应制备式3a所示的α-羟基β-硝基酰胺类化合物,探讨了不同合成条件对目标产物产率的影响,结果如表1所示。反应式如下:
以实施例10为例,典型反应操作如下:
向反应器中依次加入式1a所示的α-酮酰胺类化合物(0.1mmol)、L-精氨酸(0.02mmol)、硝基甲烷(2mmol)和水(1mL),随后将反应器置于室温下搅拌反应6小时,经TLC监测反应完全后,向反应混合液中加入二氯甲烷萃取(30mL*3),合并有机相,加入无水硫酸钠干燥,真空浓缩得到残余物,随后将残余物经硅胶柱层析分离(乙酸乙酯:正己烷,V/V=1:6)得到式3a所示的α-羟基β-硝基酰胺类化合物。白色固体(26.6mg,产率93%);1H NMR(500MHz,CDCl3)δ8.46(s,1H),7.67(d,J=7.0Hz,2H),7.50(d,J=7.5Hz,2H),7.41-7.36(m,3H),7.32-7.29(m,2H),7.13-7.10(m,1H),5.31(d,J=15.0Hz,1H),4.95(s,1H),4.76(d,J=15.0Hz,1H).13C NMR(126MHz,CDCl3)δ168.40,136.83,136.22,129.27,129.06,124.99,124.89,119.86,80.09。
表1:
实施例 | 催化剂 | 溶剂 | 时间(h) | 产率(%)b |
1 | Et3N | CH3NO2 | 24 | 20 |
2 | DBU | CH3NO2 | 24 | 49 |
3 | TMG | CH3NO2 | 24 | 64 |
4 | DMAP | CH3NO2 | 24 | 15 |
5 | 四氢吡咯 | CH3NO2 | 24 | 18 |
6 | 金鸡纳碱 | CH3NO2 | 24 | 36 |
7 | K2CO3 | CH3NO2 | 24 | 45 |
8 | KTB | CH3NO2 | 24 | 44 |
9 | L-精氨酸 | CH3NO2 | 24 | 18 |
10c | L-精氨酸 | H2O | 6 | 93 |
11 | L-精氨酸-K | H2O | 24 | 82 |
12 | TMG | H2O | 24 | 73 |
13d | L-精氨酸 | H2O | 24 | 76 |
14e | L-精氨酸 | H2O | 24 | 87 |
a反应条件:1a(0.1mmol),催化剂(0.02mmol),溶剂(1.0mL),反应温度25℃;b分离产率;cH2O作为溶剂,CH3NO2(20eq.).dCH3NO2(40eq.).eCH3NO2(10eq.)。
其中各英文缩写表示的含义如下:
DBU:1,8-二氮杂二环[5.4.0]十一碳-7-烯;
Et3N:三乙胺;
TMG:四甲基胍;
DMAP:4-二甲氨基吡啶;
KTB:叔丁醇钾。
由表1可以看出,与传统的Henry反应在碱如K2CO3、金鸡纳碱等作为催化剂的条件下相比,实施例10的方法使用水作为溶剂、L-精氨酸作为催化剂的反应体系使得本发明的方法能够取得远远更高的目标产物3a产率,同时也显著地缩短了反应所需要的时间,提高了生产效率,且本发明的优化反应条件(实施例10)使用水作为溶剂,较之传统方法显著地减少了硝基甲烷的用量,提高了原子经济性和降低了生产成本。
实施例15-36反应底物拓展试验
以实施例10的反应条件作为最优反应条件,进一步探究了在该最佳反应条件下对反应底物的适应性,即仅改变反应原料种类,其余反应条件及操作同实施例10,结果如下:
产物的结构表征:
化合物3b:白色固体(31.0mg,97%).1H NMR(400MHz,CDCl3)δ8.30(s,1H),7.74–7.67(m,1H),7.62–7.54(m,2H),7.53–7.46(m,1H),7.45–7.33(m,4H),7.19(t,J=7.5Hz,1H),5.42(d,J=14.0Hz,1H),5.28(d,J=14.0Hz,1H),5.11(s,1H).13C NMR(126MHz,CDCl3)δ167.16,136.81,133.49,132.34,132.12,130.97,129.12,129.09,127.77,125.17,120.12,78.87。
化合物3c:白色固体(31.3mg,98%).1H NMR(500MHz,CDCl3)δ8.46(s,1H),7.72(s,1H),7.56-7.49(m,3H),7.37-7.30(m,4H),7.13(t,J=7.5Hz,1H),5.29(d,J=15.0Hz,1H),5.05(s,1H),4.74(d,J=15.0Hz,1H).13C NMR(126MHz,CDCl3)δ167.81,138.15,136.62,135.24,130.29,129.52,129.11,125.32,125.18,123.18,119.92,79.86,77.55。
化合物3d:白色固体(27.2mg,86%).1H NMR(400MHz,CDCl3)δ8.49(s,1H),7.69–7.63(m,2H),7.56–7.50(m,2H),7.46–7.39(m,2H),7.39–7.32(m,2H),7.19-7.15(m,1H),5.31(d,J=14.8Hz,1H),5.08(s,1H),4.77(d,J=14.8Hz,1H).13C NMR(126MHz,CDCl3)δ168.07,136.62,135.53,134.72,129.23,129.11,126.46,125.19,119.94,79.93,77.64。
化合物3e:白色固体(21.5mg,71%).1H NMR(500MHz,CDCl3)δ8.48(s,1H),7.70–7.61(m,2H),7.49(d,J=8.0Hz,2H),7.31(t,J=8.0Hz,2H),7.14-7.07(m,3H),5.28(d,J=15.0Hz,1H),5.05(s,1H),4.73(d,J=15.0Hz,1H).13CNMR(126MHz,CDCl3)δ168.32,163.19(d,JC-F=249.6Hz),136.67,132.05(d,JC-F=3.2Hz),129.09,127.01(d,JC-F=8.5Hz),125.14,119.96,116.00(d,JC-F=12.8Hz),80.09,77.64。
化合物3f:白色固体(28.7mg,79%).1H NMR(500MHz,CDCl3)δ8.43(s,1H),7.60–7.51(m,4H),7.51–7.45(m,2H),7.32(t,J=8.0Hz,2H),7.17–7.09(m,1H),5.26(d,J=15.0Hz,1H),5.00(s,1H),4.74(d,J=15.0Hz,1H).13CNMR(126MHz,CDCl3)δ167.91,136.61,135.19,132.22,129.11,126.73,125.18,123.76,119.89,79.82。
化合物3g:白色固体(20.7mg,69%).1H NMR(500MHz,CDCl3)δ8.43(s,1H),7.54-7.48(m,4H),7.30(t,J=8.0Hz,2H),7.21(d,J=8.0Hz,2H),7.11(t,J=7.5Hz,1H),5.28(d,J=15.0Hz,1H),4.88(s,1H),4.75(d,J=15.0Hz,1H),2.34(s,3H).13C NMR(126MHz,CDCl3)δ168.60,139.27,136.86,133.32,129.72,129.05,124.93,124.79,119.84,80.13,21.06。
化合物3h:白色固体(19.9mg,63%).1H NMR(400MHz,CDCl3)δ8.50(s,1H),7.64–7.57(m,2H),7.57–7.51(m,2H),7.36-7.32(m,2H),7.19–7.11(m,1H),6.98–6.90(m,2H),5.31(d,J=14.0Hz,1H),4.97(s,1H),4.81–4.72(d,J=14.0Hz,1H),3.83(s,3H).13C NMR(126MHz,CDCl3)δ168.70,160.27,136.87,129.04,128.25,126.30,124.93,119.87,114.41,80.18,55.34。
化合物3i:白色固体(26.1mg,87%).1H NMR(500MHz,CDCl3)δ8.41(s,1H),7.75(d,J=8.0Hz,1H),7.70–7.64(m,2H),7.45–7.35(m,3H),7.22–7.13(m,2H),7.07(t,J=7.5Hz,1H),5.32(d,J=15.0Hz,1H),5.01(s,1H),4.76(d,J=15.0Hz,1H),2.16(s,3H).13C NMR(126MHz,CDCl3)δ168.60,136.51,134.61,130.53,129.29,129.23,129.04,126.81,125.69,124.84,122.57,80.11,78.09,17.36。
化合物3j:白色固体(24.6mg,82%).1H NMR(500MHz,CDCl3)δ8.43(s,1H),7.71–7.62(m,2H),7.44–7.34(m,4H),7.27-7.25(m,1H),7.18(t,J=8.0Hz,1H),6.93(d,J=7.5Hz,1H),5.30(d,J=15.0Hz,1H),4.96(s,1H),4.74(d,J=15.0Hz,1H),2.31(s,3H).13CNMR(126MHz,CDCl3)δ168.41,139.09,136.74,136.30,129.25,129.05,128.88,125.79,124.90,120.48,116.94,80.11,78.02,21.40。
化合物3k:白色固体(25.5mg,85%).1H NMR(500MHz,CDCl3)δ8.44(s,1H),7.72–7.60(m,2H),7.47–7.32(m,5H),7.09(d,J=8.0Hz,2H),5.29(d,J=14.5Hz,1H),4.98(s,1H),4.74(d,J=14.5Hz,1H),2.29(s,3H).13C NMR(126MHz,CDCl3)δ168.33,136.39,134.71,134.24,129.61,129.53,129.21,129.01,124.92,119.94,80.16,77.97,20.86。
化合物3m:白色固体(26.2mg,83%).1H NMR(500MHz,CDCl3)δ8.39(s,1H),7.65(d,J=7.5Hz,2H),7.44–7.33(m,5H),6.83(d,J=9.0Hz,2H),5.30(d,J=14.5Hz,1H),4.95(s,1H),4.75(d,J=14.5Hz,1H),3.76(s,3H).13C NMR(126MHz,CDCl3)δ168.25,156.91,136.43,129.91,129.21,129.02,124.91,121.66,114.24,80.18,77.94,55.49。
化合物3n:白色固体(25.2mg,83%).1H NMR(500MHz,CDCl3)δ8.46(s,1H),7.71–7.62(m,2H),7.52–7.35(m,5H),7.02-6.98(m,2H),5.31(d,J=15.0Hz,1H),4.96(s,1H),4.75(d,J=15.0Hz,1H).13C NMR(126MHz,CDCl3)δ168.46,159.74(d,JC-F=244.5Hz),136.11,132.80(d,JC-F=2.9Hz),129.33,129.09,124.85,121.71(d,JC-F=7.9Hz),115.75(d,JC-F=22.6Hz),80.09。
化合物3o:白色固体(23.0mg,72%).1H NMR(500MHz,CDCl3)δ8.46(s,1H),7.70–7.62(m,2H),7.49–7.36(m,5H),7.31–7.24(m,2H),5.30(d,J=15.0Hz,1H),4.95(s,1H),4.76(d,J=15.0Hz,1H).13C NMR(126MHz,CDCl3)δ168.48,135.96,135.38,130.09,129.39,129.12,129.10,124.84,121.09,80.02。
化合物3p:白色固体(28.0mg,77%yield).1H NMR(500MHz,CDCl3)δ8.46(s,1H),7.69-7.61(m,2H),7.47–7.33(m,7H),5.30(d,J=15.0Hz,1H),4.95(s,1H),4.76(d,J=15.0Hz,1H).13C NMR(126MHz,CDCl3)δ168.50,135.93,135.89,132.06,129.40,129.13,124.84,121.40,117.71,80.01。
化合物3q:白色固体(31.7mg,77%yield).1H NMR(500MHz,CDCl3)δ8.45(s,1H),7.71–7.57(m,4H),7.47–7.36(m,3H),7.32-7.27(m,2H),5.30(d,J=14.8Hz,1H),4.97(s,1H),4.76(d,J=14.7Hz,1H).13C NMR(126MHz,CDCl3)δ168.49,138.00,136.59,135.92,129.38,129.11,124.83,121.64,88.32,80.00。
化合物3r:白色固体(23.7mg,85%yield).1H NMR(500MHz,CDCl3)δ9.14(s,1H),8.31(dd,J=8.0,1.5Hz,1H),7.77–7.64(m,2H),7.46–7.31(m,3H),7.05(td,J=8.0,1.5Hz,1H),6.93(t,J=8.0Hz,1H),6.86(d,J=8.0,1H),5.32(d,J=15.0Hz,1H),4.91(s,1H),4.77(d,J=15.0Hz,1H),3.86(s,3H).13CNMR(126MHz,CDCl3)δ168.19,148.31,136.44,129.13,128.97,126.66,124.93,124.53,120.98,119.54,110.07,80.16,55.76。
化合物3s:白色固体(20.7mg,68%yield).1H NMR(400MHz,CDCl3)δ8.83(s,1H),8.30-8.26(m,1H),7.72-7.69(m,2H),7.51–7.38(m,3H),7.20–7.06(m,3H),5.37(d,J=14.8Hz,1H),5.05(s,1H),4.82(d,J=14.8Hz,1H).13CNMR(126MHz,CDCl3)δ168.63,152.66(d,J=244.8Hz),136.04,129.33,129.09,125.42(d,J=10.2Hz),125.15(d,J=7.6Hz),124.86,124.57(d,J=3.9Hz),121.38,114.98(d,J=19.0Hz),80.03,78.09。
化合物3t:白色固体(29.1mg,80%yield).1H NMR(500MHz,CDCl3)δ9.14(s,1H),8.27-8.25(m,1H),7.73–7.64(m,2H),7.52-7.50(m,1H),7.47–7.35(m,3H),7.32–7.26(m,1H),7.00-6.96(m,1H),5.34(d,J=15.0Hz,1H),5.01(s,1H),4.81(d,J=15.0Hz,1H).13CNMR(126MHz,CDCl3)δ168.68,136.09,134.81,132.39,129.32,129.11,128.36,125.85,124.85,121.56,114.01,79.96,78.16。
化合物3v:白色固体(20.3mg,91%yield).1H NMR(500MHz,CDCl3)δ8.63(s,1H),7.60–7.48(m,2H),7.42–7.31(m,2H),7.21–7.11(m,1H),5.03(d,J=13.8Hz,1H),4.55(d,J=13.8Hz,1H),4.24(s,1H),1.56(s,3H).13C NMR(126MHz,CDCl3)δ170.20,136.74,129.13,125.13,120.10,80.51,74.64,24.16。
化合物3u:白色固体(18.3mg,61%).1H NMR(500MHz,CDCl3)δ8.37(s,1H),7.67-7.65(m,2H),7.41-7.35(m,3H),7.31(s,1H),7.20-7.19(m,1H),7.05-7.04(m,1H),5.29(d,J=14.5Hz,1H),4.93(s,1H),4.75(d,J=14.5Hz,1H),2.21(s,3H),2.20(s,3H).13C NMR(126MHz,CDCl3)δ168.22,137.38,136.37,134.52,133.39,130.00,129.20,129.02,124.91,121.13,117.32,80.13,19.79,19.16。
以上所述实施例仅为本发明的优选实施例,而并非本发明可行实施的穷举。对于本领域技术人员而言,在不背离本发明原理和精神的前提下,对其所作出的任何显而易见的改动,都应当被认为包含在本发明的权利要求保护范围之内。
Claims (7)
1.一种α-羟基β-硝基酰胺类化合物的合成方法,其特征在于,包括如下步骤:
向反应器中加入式1所示的α-酮酰胺类化合物、式2所示的硝基甲烷、L-精氨酸和溶剂水,随后将反应器在室温下搅拌反应,反应完全后经纯化处理得到式3所示的α-羟基β-硝基酰胺类化合物,反应式如下:
上述反应式中,R1,R2彼此独立地选自C1-20烷基、取代或未取代的C6-12芳基;所述取代或未取代的中的取代基选自氟、氯、溴、碘、甲基、乙基、甲氧基、乙氧基。
2.根据权利要求1所述的合成方法,其特征在于,式1化合物选自如下化合物:
3.根据权利要求1所述的合成方法,其特征在于,式1所示的α-酮酰胺类化合物、式2所示的硝基甲烷、L-精氨酸的投料摩尔比为1:(5~40):(0.1~0.3)。
4.根据权利要求3所述的合成方法,其特征在于,式1所示的α-酮酰胺类化合物、式2所示的硝基甲烷、L-精氨酸的投料摩尔比为1:20:0.2。
5.根据权利要求1所述的合成方法,其特征在于,所述搅拌反应的反应时间为4~48h。
6.根据权利要求5所述的合成方法,其特征在于,所述搅拌反应的反应时间为6~24h。
7.根据权利要求1所述的合成方法,其特征在于,所述纯化处理具体操作如下:反应完全后向反应液中加入二氯甲烷萃取,合并有机相,干燥、浓缩、用乙酸乙酯和正己烷作为洗脱溶剂经硅胶柱层析分离得到式3所示的α-羟基β-硝基酰胺类化合物。
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