CN113512064A - Preparation method of aromatic phosphine oxide compound - Google Patents
Preparation method of aromatic phosphine oxide compound Download PDFInfo
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- CN113512064A CN113512064A CN202110477852.XA CN202110477852A CN113512064A CN 113512064 A CN113512064 A CN 113512064A CN 202110477852 A CN202110477852 A CN 202110477852A CN 113512064 A CN113512064 A CN 113512064A
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- phosphine oxide
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- -1 aromatic phosphine oxide compound Chemical class 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 239000012074 organic phase Substances 0.000 claims abstract description 25
- 239000003513 alkali Substances 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 21
- 238000004440 column chromatography Methods 0.000 claims abstract description 18
- 238000005406 washing Methods 0.000 claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 16
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 11
- 238000001035 drying Methods 0.000 claims abstract description 11
- 238000003756 stirring Methods 0.000 claims abstract description 11
- 239000011259 mixed solution Substances 0.000 claims abstract description 10
- 238000001816 cooling Methods 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 6
- 238000002156 mixing Methods 0.000 claims abstract description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 16
- 239000012043 crude product Substances 0.000 claims description 16
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 239000012298 atmosphere Substances 0.000 claims description 10
- 238000004821 distillation Methods 0.000 claims description 9
- YFPJFKYCVYXDJK-UHFFFAOYSA-N Diphenylphosphine oxide Chemical compound C=1C=CC=CC=1[P+](=O)C1=CC=CC=C1 YFPJFKYCVYXDJK-UHFFFAOYSA-N 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- CWLKTJOTWITYSI-UHFFFAOYSA-N 1-fluoronaphthalene Chemical compound C1=CC=C2C(F)=CC=CC2=C1 CWLKTJOTWITYSI-UHFFFAOYSA-N 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- UNNNAIWPDLRVRN-UHFFFAOYSA-N 1-fluoro-4-(trifluoromethyl)benzene Chemical compound FC1=CC=C(C(F)(F)F)C=C1 UNNNAIWPDLRVRN-UHFFFAOYSA-N 0.000 claims description 3
- MTAODLNXWYIKSO-UHFFFAOYSA-N 2-fluoropyridine Chemical compound FC1=CC=CC=N1 MTAODLNXWYIKSO-UHFFFAOYSA-N 0.000 claims description 3
- CELKOWQJPVJKIL-UHFFFAOYSA-N 3-fluoropyridine Chemical compound FC1=CC=CN=C1 CELKOWQJPVJKIL-UHFFFAOYSA-N 0.000 claims description 3
- AEKVBBNGWBBYLL-UHFFFAOYSA-N 4-fluorobenzonitrile Chemical compound FC1=CC=C(C#N)C=C1 AEKVBBNGWBBYLL-UHFFFAOYSA-N 0.000 claims description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 3
- GPIARMSVZOEZCV-UHFFFAOYSA-N 6-fluoro-2-methylquinoline Chemical compound C1=C(F)C=CC2=NC(C)=CC=C21 GPIARMSVZOEZCV-UHFFFAOYSA-N 0.000 claims description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 3
- RREGWFNURZJKNB-UHFFFAOYSA-N bis(4-methoxyphenyl)-oxophosphanium Chemical compound C1=CC(OC)=CC=C1[P+](=O)C1=CC=C(OC)C=C1 RREGWFNURZJKNB-UHFFFAOYSA-N 0.000 claims description 3
- ZHIPXAFNKGZMSC-UHFFFAOYSA-N bis(4-methylphenyl)-oxophosphanium Chemical compound C1=CC(C)=CC=C1[P+](=O)C1=CC=C(C)C=C1 ZHIPXAFNKGZMSC-UHFFFAOYSA-N 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 239000002274 desiccant Substances 0.000 claims description 3
- JMCNGFNJWDJIIV-UHFFFAOYSA-N dibutyl(oxo)phosphanium Chemical compound CCCC[P+](=O)CCCC JMCNGFNJWDJIIV-UHFFFAOYSA-N 0.000 claims description 3
- HJPHBJYOODQSLK-UHFFFAOYSA-N dicyclohexyl(oxo)phosphanium Chemical compound C1CCCCC1[P+](=O)C1CCCCC1 HJPHBJYOODQSLK-UHFFFAOYSA-N 0.000 claims description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000005493 quinolyl group Chemical group 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 239000012535 impurity Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 150000001491 aromatic compounds Chemical class 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 42
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 239000003054 catalyst Substances 0.000 abstract description 3
- 239000003446 ligand Substances 0.000 abstract description 3
- 239000000654 additive Substances 0.000 abstract 1
- 230000000996 additive effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 150000003839 salts Chemical class 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 229910052739 hydrogen Inorganic materials 0.000 description 10
- 239000001257 hydrogen Substances 0.000 description 10
- 238000001228 spectrum Methods 0.000 description 10
- 239000000047 product Substances 0.000 description 9
- 238000000926 separation method Methods 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 229910052723 transition metal Inorganic materials 0.000 description 6
- 150000003624 transition metals Chemical class 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- AUONHKJOIZSQGR-UHFFFAOYSA-N oxophosphane Chemical compound P=O AUONHKJOIZSQGR-UHFFFAOYSA-N 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 3
- 231100000086 high toxicity Toxicity 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 239000011574 phosphorus Substances 0.000 description 3
- 238000007789 sealing Methods 0.000 description 3
- MZTZOWNHEQNCAG-UHFFFAOYSA-N 1-bis(4-methoxyphenyl)phosphorylnaphthalene Chemical compound C1=CC(OC)=CC=C1P(=O)(C=1C2=CC=CC=C2C=CC=1)C1=CC=C(OC)C=C1 MZTZOWNHEQNCAG-UHFFFAOYSA-N 0.000 description 2
- MUPFLVJSBOXAIZ-UHFFFAOYSA-N 1-bis(4-methylphenyl)phosphorylnaphthalene Chemical compound C1(=CC=CC2=CC=CC=C12)P(C1=CC=C(C=C1)C)(C1=CC=C(C=C1)C)=O MUPFLVJSBOXAIZ-UHFFFAOYSA-N 0.000 description 2
- BEQVHTHRNGNDFV-UHFFFAOYSA-N 1-dibutylphosphorylnaphthalene Chemical compound C1=CC=C2C(P(=O)(CCCC)CCCC)=CC=CC2=C1 BEQVHTHRNGNDFV-UHFFFAOYSA-N 0.000 description 2
- WGWYEVGQPCDUDG-UHFFFAOYSA-N 1-dicyclohexylphosphorylnaphthalene Chemical compound C1(CCCCC1)P(C1=CC=CC2=CC=CC=C12)(C1CCCCC1)=O WGWYEVGQPCDUDG-UHFFFAOYSA-N 0.000 description 2
- SHAMDBARMGINAU-UHFFFAOYSA-N 1-diphenylphosphoryl-4-(trifluoromethyl)benzene Chemical compound C1=CC(C(F)(F)F)=CC=C1P(=O)(C=1C=CC=CC=1)C1=CC=CC=C1 SHAMDBARMGINAU-UHFFFAOYSA-N 0.000 description 2
- QPFFMCFXDHYNFR-UHFFFAOYSA-N 1-diphenylphosphorylnaphthalene Chemical compound C=1C=CC=CC=1P(C=1C2=CC=CC=C2C=CC=1)(=O)C1=CC=CC=C1 QPFFMCFXDHYNFR-UHFFFAOYSA-N 0.000 description 2
- DNWSVXHWEWBVSJ-UHFFFAOYSA-N 2-diphenylphosphorylpyridine Chemical compound C=1C=CC=CC=1P(C=1N=CC=CC=1)(=O)C1=CC=CC=C1 DNWSVXHWEWBVSJ-UHFFFAOYSA-N 0.000 description 2
- SVBRQYHOHVTPIB-UHFFFAOYSA-N 3-diphenylphosphorylpyridine Chemical compound C=1C=CC=CC=1P(C=1C=NC=CC=1)(=O)C1=CC=CC=C1 SVBRQYHOHVTPIB-UHFFFAOYSA-N 0.000 description 2
- HACFJDUFXXBVMD-UHFFFAOYSA-N 4-diphenylphosphorylbenzonitrile Chemical compound C=1C=CC=CC=1P(C=1C=CC(=CC=1)C#N)(=O)C1=CC=CC=C1 HACFJDUFXXBVMD-UHFFFAOYSA-N 0.000 description 2
- AILRADAXUVEEIR-UHFFFAOYSA-N 5-chloro-4-n-(2-dimethylphosphorylphenyl)-2-n-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]pyrimidine-2,4-diamine Chemical compound COC1=CC(N2CCC(CC2)N2CCN(C)CC2)=CC=C1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1P(C)(C)=O AILRADAXUVEEIR-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229950004272 brigatinib Drugs 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 238000006880 cross-coupling reaction Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- XBHPFCIWRHJDCP-UHFFFAOYSA-N (2-trimethylsilylphenyl) trifluoromethanesulfonate Chemical compound C[Si](C)(C)C1=CC=CC=C1OS(=O)(=O)C(F)(F)F XBHPFCIWRHJDCP-UHFFFAOYSA-N 0.000 description 1
- PSIRFUPZHPEKAE-UITAMQMPSA-N (nz)-n-[(2-bromophenyl)methylidene]hydroxylamine Chemical compound O\N=C/C1=CC=CC=C1Br PSIRFUPZHPEKAE-UITAMQMPSA-N 0.000 description 1
- UVTXHAOLTBFLDL-UHFFFAOYSA-N 4-[(4-carboxyphenyl)-phenylphosphoryl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1P(=O)(C=1C=CC(=CC=1)C(O)=O)C1=CC=CC=C1 UVTXHAOLTBFLDL-UHFFFAOYSA-N 0.000 description 1
- 229940122531 Anaplastic lymphoma kinase inhibitor Drugs 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical class OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
- C07F9/5325—Aromatic phosphine oxides or thioxides (P-C aromatic linkage)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/58—Pyridine rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/60—Quinoline or hydrogenated quinoline ring systems
Abstract
The invention relates to the field of organic synthesis, in particular to a preparation method of an aromatic phosphine oxide compound. The preparation method comprises the following steps: adding a P (O) -H compound, a fluoro-aromatic compound and an alkali reagent into an organic solvent for mixing, stirring for reaction, and cooling to obtain a mixed solution; washing and extracting to obtain an organic phase, drying and distilling the organic phase, and then carrying out column chromatography to obtain the aromatic phosphine oxide compound. The reaction operation method is simple, only a proper amount of alkali is needed to be added, special reaction conditions such as a ligand, a catalyst and an additive are not needed, the reaction is simple and efficient, and the method has a good industrial application prospect.
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to a preparation method of an aromatic phosphine oxide compound.
Background
The organic phosphine compound containing the phosphorus-carbon bond is an important organic synthesis raw material and intermediate, and is widely applied to the fields of material chemistry, organic synthesis, medicinal chemistry and the like. Such as bis (4-carboxyphenyl) phenylphosphine oxide (BCPPO), are widely used for flame retardation of polyesters. The FDA approved new oral ALK inhibitor, Brigatinib (Brigatinib), for lung cancer therapy in 2017, which has a structural species containing both aryl and alkyl carbon-phosphorus bonds (Huang W-S, Liu S, Zou D, et al. journal of Medicinal Chemistry,2016,59(10): 4948-. Chinese patent CN106674282A discloses a P2Y12 receptor antagonist containing an aryl phosphine oxide structure for treating cardiovascular diseases. Therefore, it is of great interest to develop efficient synthetic methods for such compounds.
The traditional method for synthesizing the aromatic phosphine oxide compound generally needs to use a phosphorus halide compound and an organic metal reagent to carry out nucleophilic substitution reaction, and the reaction has the characteristics of high toxicity, high activity and sensitivity to water and oxygen and is not easy to store and operate. The construction of P-C bond by transition metal catalyzed P (O) -H compound and coupling reagent direct cross-coupling reaction is also an important method for preparing the compound. For example, palladium catalysis can be used to realize cross-coupling of P (O) -H compound and iodo-arene, bromo-arene or chloro-arene compound to synthesize important aromatic phosphine oxide compounds (Rummelt S, Ranocchiari M, van Bokhoven J A. organic Letters,2012,14(8):2188-2190.Xu K, Yang F, Zhang G, et al. Green Chemistry,2013,15(4): 1055-. Chinese patent CN110540552A discloses a novel method for efficiently synthesizing aromatic phosphine oxide compounds by nickel-catalyzed reaction of aromatic carboxylic acid compounds and P (O) -H compounds, which can be used for preparing small molecule drugs. In addition, chinese patent CN109369716A discloses a method for synthesizing aromatic phosphine oxide by using aryne precursor (2- (trimethylsilyl) phenyl trifluoromethanesulfonate) and diarylphosphinic acid under the action of alkali and fluorine source, which has mild conditions and a certain substrate application range.
The reported or disclosed methods for the synthesis of aromatic phosphine oxides mainly suffer from the following disadvantages: the phosphorus halide reagent has high toxicity, is sensitive to water and oxygen and has harsh reaction conditions; secondly, a transition metal catalyst and a ligand are needed, so that the cost is high and the environment is not green enough; part of the raw materials are expensive or need to be pre-functionalized, and the reaction steps are complex.
Disclosure of Invention
Based on the above, the invention provides a novel method for synthesizing aromatic phosphine oxide compounds, which is simple and efficient and does not need transition metal catalysts and ligands, aiming at the defects of the prior art.
The invention provides a preparation method of an aromatic phosphine oxide compound, which comprises the following steps:
adding a P (O) -H compound, a fluoro aromatic compound and an alkali reagent into an organic solvent under an inert atmosphere, mixing, stirring and reacting at 60-140 ℃ for 10-24H, and cooling to obtain a mixed solution;
washing and extracting the mixed solution to obtain an organic phase, drying and distilling the organic phase, and then carrying out column chromatography to obtain an aromatic phosphine oxide compound;
the P (O) -H compound is diphenyl phosphine oxide, bis (4-methylphenyl) phosphine oxide, bis (4-methoxyphenyl) phosphine oxide, di-n-butyl phosphine oxide, dicyclohexylphosphine oxide;
the fluorinated aromatic hydrocarbon compound is 1-fluoronaphthalene, 2-fluoropyridine, 3-fluoropyridine, 4-fluorobenzonitrile, 4-fluoro-benzotrifluoride and 6-fluoro-2-methylquinoline;
the structural formula of the aromatic phosphine oxide compound is as follows:
wherein R is trifluoromethyl, cyano or aryl and is one of naphthyl, pyridyl and substituted quinolyl; r2Or R3Is one of phenyl, 4-methylphenyl, 4-methoxyphenyl, n-butyl or cyclohexyl.
Furthermore, the molar ratio of the P (O) -H compound, the fluoro-aromatic compound and the alkali reagent is 1: 1-2: 1-3.
Further, the alkali reagent is one or two of sodium tert-butoxide and potassium tert-butoxide.
Further, the organic solvent is one or more of toluene, N-dimethylformamide, 1, 4-dioxane and tetrahydrofuran.
Further, the steps of washing and extracting the mixed solution to obtain an organic phase, drying and distilling the organic phase, and then performing column chromatography to obtain the aromatic phosphine oxide compound specifically comprise:
washing the mixed solution with water, removing water-soluble impurities, and adding an extracting agent for extraction to obtain an organic phase;
adding a drying agent into the organic phase for drying, and removing the solvent by reduced pressure distillation to obtain a crude product of the aromatic phosphine oxide compound;
and (3) separating the crude product of the aromatic phosphine oxide compound by column chromatography to obtain the aromatic phosphine oxide compound.
Has the advantages that:
(1) the invention provides a method for preparing aromatic phosphine oxide compounds directly from P (O) -H compounds and fluoroarene in one step, wherein the P (O) -H compounds adopted in the preparation process are simple and easily obtained, more green and stable, and have higher atom economy compared with phosphorus halide reagents, and reactants of fluoroarene have wide sources and lower cost.
(2) The aromatic phosphine oxide preparation process has simple reaction conditions, can efficiently carry out the reaction by adding a certain amount of alkaline reagents such as potassium tert-butoxide and the like, and has high reaction yield of 61-95 percent. The method avoids the problems of high toxicity of raw materials, harsh reaction conditions and narrow applicability of substrates in the synthesis method in the prior art, avoids the use of transition metals, solves the problems of high cost of the transition metals, complex operation caused by sensitivity of part of the transition metals in the air and the like, has environmental protection and economy, and is suitable for industrial popularization.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the disclosure.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of diphenyl (1-naphthyl) phosphine oxide obtained in example 1;
FIG. 2 is a nuclear magnetic hydrogen spectrum of diphenyl (2-pyridyl) phosphine oxide obtained in example 2;
FIG. 3 is a nuclear magnetic hydrogen spectrum of diphenyl (3-pyridyl) phosphine oxide obtained in example 3;
FIG. 4 is a nuclear magnetic hydrogen spectrum of diphenyl (4-cyanophenyl) phosphine oxide obtained in example 4;
FIG. 5 is a nuclear magnetic hydrogen spectrum of diphenyl (4-trifluoromethylphenyl) phosphine oxide obtained in example 5;
FIG. 6 is a nuclear magnetic hydrogen spectrum of diphenyl (2-methyl-6-quinolyl) phosphine oxide obtained in example 6;
FIG. 7 is a nuclear magnetic hydrogen spectrum of bis (4-methylphenyl) (1-naphthyl) phosphine oxide obtained in example 7;
FIG. 8 is a nuclear magnetic hydrogen spectrum of bis (4-methoxyphenyl) (1-naphthyl) phosphine oxide obtained in example 8;
FIG. 9 is a nuclear magnetic hydrogen spectrum of di-n-butyl (1-naphthyl) phosphine oxide obtained in example 9;
FIG. 10 is a nuclear magnetic hydrogen spectrum of dicyclohexyl (1-naphthyl) phosphine oxide obtained in example 10.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
In the present example, the aromatic phosphine oxide production process was carried out as shown in the reaction formula (1).
Wherein R is trifluoromethyl, cyano or aryl and is one of naphthyl, pyridyl and substituted quinolyl; r2Or R3Is one of phenyl, 4-methylphenyl, 4-methoxyphenyl, n-butyl or cyclohexyl.
In the embodiment of the invention, the synthesis steps of the aromatic phosphine oxide by using the P (O) -H compound and the fluorinated aromatic hydrocarbon are as follows:
under the inert atmosphere, putting fluoro aromatic hydrocarbon, an alkali reagent, a P (O) -H compound and an organic solvent into a reaction container, mixing, continuously stirring for reaction for 10-24H at the reaction temperature of 60-140 ℃, and cooling to room temperature after the reaction is finished to obtain a mixture;
washing the mixed solution with water to remove excessive alkali and generated salt in the reaction, extracting with an extracting agent to obtain an organic phase, drying with a drying agent, and then distilling under reduced pressure to remove the solvent to obtain a crude product of the aromatic phosphine oxide compound; and separating the crude product by column chromatography to obtain the aromatic phosphine oxide compound.
The following examples are further illustrative.
Example 1
This example provides a method for preparing diphenyl (1-naphthyl) phosphine oxide, which comprises the following steps:
under the atmosphere of nitrogen, 0.20mmol of diphenylphosphine oxide, 0.20mmol of 1-fluoronaphthalene, 0.30mmol of potassium tert-butoxide and 1.5mL of toluene solvent are added into a reactor, the reactor is heated to 120 ℃ after being sealed, the stirring is continued for 20 hours, the reaction is stopped, the reactor is cooled to room temperature, excessive alkali and generated salt in the reaction are removed by washing, dichloromethane is used for extracting a water phase to obtain an organic phase, anhydrous sodium sulfate is dried, the solvent is removed by reduced pressure distillation, a crude product is separated by column chromatography to obtain a target product, and the separation yield is 90%.1H NMR(400MHz CDCl3) Delta 8.58(d, J-8.4 Hz,1H),8.02(d, J-8.4 Hz,1H),7.89(d, J-8.0 Hz,1H), 7.71-7.66 (m,4H), 7.57-7.44 (m,8H), 7.42-7.36 (m,1H), 7.33-7.27 (m,1H), the detailed map is shown in figure 1.
Example 2
This example provides a method for preparing diphenyl (2-pyridyl) phosphine oxide, which comprises the following steps:
adding 0.20mmol of diphenylphosphine oxide, 0.20mmol of 2-fluoropyridine, 0.30mmol of potassium tert-butoxide and 1.5mL of toluene solvent into a reactor under the nitrogen atmosphere, sealing the reactor, heating to 120 ℃, continuously stirring for 20 hours, stopping the reaction, cooling to room temperature, washing to remove excessive alkali and generated salt in the reaction, extracting the water phase with dichloromethane to obtain an organic phase, drying with anhydrous sodium sulfate, distilling under reduced pressure to remove the solvent, and separating the crude product by column chromatography to obtain the target productProduct, isolation yield 95%.1H NMR(400MHz CDCl3) Delta 8.75(d, J is 4.4Hz,1H),8.29(t, J is 6.8Hz,1H), 7.91-7.86 (m,4H), 7.84-7.80 (m,1H), 7.52-7.41 (m,6H), 7.37-7.34 (m,1H), and the detailed map is shown in the attached figure 2.
Example 3
This example provides a method for preparing diphenyl (3-pyridyl) phosphine oxide, which comprises the following steps:
under the atmosphere of nitrogen, 0.20mmol of diphenylphosphine oxide, 0.20mmol of 3-fluoropyridine, 0.30mmol of potassium tert-butoxide and 1.5mL of toluene solvent are added into a reactor, the reactor is heated to 120 ℃ after being sealed, the stirring is continued for 20 hours, the reaction is stopped, the reactor is cooled to room temperature, excessive alkali and generated salt in the reaction are removed by washing, dichloromethane is used for extracting an aqueous phase to obtain an organic phase, anhydrous sodium sulfate is dried, the solvent is removed by reduced pressure distillation, a crude product is separated by column chromatography to obtain a target product, and the separation yield is 94%.1H NMR(400MHz CDCl3) Delta 8.78-8.77 (m,2H), 8.08-8.03 (m,1H), 7.71-7.66 (m,4H), 7.59-7.56 (m,2H), 7.52-7.47 (m,4H), 7.44-7.41 (m,1H), and the detailed map is shown in figure 3.
Example 4
This example provides a method for preparing diphenyl (4-cyanophenyl) phosphine oxide, which comprises the following steps:
under the atmosphere of nitrogen, 0.20mmol of diphenyl phosphine oxide, 0.20mmol of 4-fluorobenzonitrile, 0.30mmol of potassium tert-butoxide and 1.5mL of toluene solvent are added into a reactor, the reactor is heated to 120 ℃ after being sealed, the stirring is continued for 20 hours, the reaction is stopped, the reaction is cooled to room temperature, excessive alkali and generated salt in the reaction are removed by washing, dichloromethane is used for extracting a water phase to obtain an organic phase, anhydrous sodium sulfate is dried, the solvent is removed by reduced pressure distillation, a crude product is separated by column chromatography to obtain a target product, and the separation yield is 70%.1HNMR(400MHz,CDCl3) δ 7.77-7.64 (m,4H), 7.62-7.48 (m,6H),7.42(d, J ═ 5.6Hz,4H), and the detailed map is shown in fig. 4.
Example 5
This example provides a method for preparing diphenyl (4-trifluoromethylphenyl) phosphine oxide, which comprises the following steps:
under nitrogen atmosphere, in the reactionAdding 0.20mmol of diphenylphosphine oxide, 0.20mmol of 4-fluorotrifluorotoluene, 0.30mmol of potassium tert-butoxide and 1.5mL of toluene solvent into a reactor, sealing the reactor, heating to 120 ℃, continuously stirring for 20 hours, stopping the reaction, cooling to room temperature, washing with water to remove excessive alkali and generated salt in the reaction, extracting the water phase with dichloromethane to obtain an organic phase, drying with anhydrous sodium sulfate, distilling under reduced pressure to remove the solvent, and separating the crude product by column chromatography to obtain the target product with the separation yield of 77%.1HNMR(400MHz CDCl3) Delta 7.85-7.80 (m,2H), 7.74-7.64 (m,6H), 7.60-7.56 (m,2H) and 7.51-7.47 (m,4H), and the detailed map is shown in figure 5.
Example 6
This example provides a method for preparing diphenyl (2-methyl-6-quinolyl) phosphine oxide, which comprises the following steps:
under the nitrogen atmosphere, 0.20mmol of diphenylphosphine oxide, 0.20mmol of 6-fluoro-2-methylquinoline, 0.30mmol of potassium tert-butoxide and 1.5mL of toluene solvent are added into a reactor, the mixture is heated to 120 ℃ after the tube is sealed, the mixture is continuously stirred for 20 hours, the reaction is stopped, the mixture is cooled to room temperature, excessive alkali and generated salt in the reaction are removed by washing, dichloromethane is used for extracting an aqueous phase to obtain an organic phase, anhydrous sodium sulfate is dried, the solvent is removed by reduced pressure distillation, and a crude product is separated by column chromatography to obtain a target product with the separation yield of 61%.1H NMR(400MHz CDCl3) δ 8.20(d, J ═ 13.2Hz,1H),7.98(d, J ═ 8.4Hz,2H), 7.73-7.68 (m,1H), 7.64-7.59 (m,4H), 7.48-7.36 (m,6H),7.25(d, J ═ 8.4Hz,1H),2.66(s,3H), the detailed map is shown in fig. 6.
Example 7
This example provides a method for preparing bis (4-methylphenyl) (1-naphthyl) phosphine oxide, which comprises the following steps:
adding 0.20mmol of bis (4-methylphenyl) phosphine oxide, 0.20mmol of 1-fluoronaphthalene, 0.30mmol of potassium tert-butoxide and 1.5mL of toluene solvent into a reactor under the atmosphere of nitrogen, sealing the reactor, heating to 120 ℃, continuously stirring for 20h, stopping the reaction, cooling to room temperature, washing with water to remove excessive alkali and generated salt in the reaction, extracting an aqueous phase with dichloromethane to obtain an organic phase, drying with anhydrous sodium sulfate, distilling under reduced pressure to remove the solvent, separating a crude product by column chromatography to obtain a target product, separating and collecting the target productThe rate was 89%.1H NMR(400MHz CDCl3) δ 8.60(d, J ═ 8.4Hz,1H),7.99(d, J ═ 8.0Hz,1H),7.87(d, J ═ 8.0Hz,1H), 7.58-7.53 (m,4H), 7.50-7.46 (m,1H), 7.45-7.41 (m,1H), 7.39-7.34 (m,1H), 7.33-7.29 (m,1H), 7.26-7.24 (m,4H),2.40(s,6H), and a detailed map is shown in fig. 7.
Example 8
This example provides a method for preparing bis (4-methoxyphenyl) (1-naphthyl) phosphine oxide, which comprises the following steps:
under the atmosphere of nitrogen, 0.20mmol of bis (4-methoxyphenyl) phosphine oxide, 0.20mmol of 1-fluoronaphthalene, 0.30mmol of potassium tert-butoxide and 1.5mL of toluene solvent are added into a reactor, the reactor is sealed and heated to 120 ℃, the reaction is continuously stirred for 20 hours, the reaction is stopped, the reaction is cooled to room temperature, excessive alkali and generated salt in the reaction are removed by washing, dichloromethane is used for extracting an aqueous phase to obtain an organic phase, anhydrous sodium sulfate is dried, the solvent is removed by reduced pressure distillation, a crude product is separated by column chromatography to obtain a target product, and the separation yield is 64%.1H NMR(400MHz,CDCl3) δ 8.61(d, J ═ 8.3Hz,1H),7.98(d, J ═ 8.0Hz,1H),7.87(d, J ═ 7.9Hz,1H),7.58(dd, J ═ 11.5,8.8Hz,4H), 7.50-7.24 (m,4H),6.95(dd, J ═ 8.8,2.1Hz,4H),3.82(s,6H), the detailed map is shown in fig. 8.
Example 9
This example provides a method for preparing di-n-butyl (1-naphthyl) phosphine oxide, which comprises the following steps:
under the atmosphere of nitrogen, 0.20mmol of di-n-butyl phosphine oxide, 0.20mmol of 1-fluoronaphthalene, 0.30mmol of potassium tert-butoxide and 1.5mL of toluene solvent are added into a reactor, the mixture is heated to 120 ℃ after being sealed, the mixture is continuously stirred for 20 hours, the reaction is stopped, the mixture is cooled to room temperature, excessive alkali and generated salt in the reaction are removed by washing, dichloromethane is used for extracting a water phase to obtain an organic phase, anhydrous sodium sulfate is dried, the solvent is removed by reduced pressure distillation, the crude product is separated by column chromatography to obtain a target product, and the separation yield is 68%.1H NMR(400MHz,CDCl3) δ 8.59(d, J ═ 8.2Hz,1H), 8.13-7.77 (m,3H), 7.71-7.45 (m,3H),2.14(dt, J ═ 19.7,10.2Hz,4H), 1.70-1.54 (m,2H), 1.51-1.30 (m,6H),0.85(t, J ═ 7.2Hz,6H), with the detailed map shown in fig. 9.
Example 10
This example provides a method for preparing dicyclohexyl (1-naphthyl) phosphine oxide, which comprises the following steps:
under the atmosphere of nitrogen, 0.20mmol of dicyclohexylphosphine oxide, 0.20mmol of 1-fluoronaphthalene, 0.30mmol of potassium tert-butoxide and 1.5mL of toluene solvent are added into a reactor, the reactor is heated to 120 ℃ after being sealed, the stirring is continued for 20 hours, the reaction is stopped, the reaction is cooled to room temperature, excessive alkali and generated salt in the reaction are removed by washing, dichloromethane is used for extracting an aqueous phase to obtain an organic phase, anhydrous sodium sulfate is dried, the solvent is removed by reduced pressure distillation, a crude product is separated by column chromatography to obtain a target product, and the separation yield is 82%.1H NMR(400MHz,CDCl3) δ 8.90(s,1H),7.89(d, J ═ 8.1Hz,1H),7.79(d, J ═ 7.9Hz,1H),7.70(s,1H),7.46(dt, J ═ 20.1,7.0Hz,3H), 2.24-1.99 (m,4H),1.74(d, J ═ 11.0Hz,2H),1.55(dd, J ═ 30.4,15.0Hz,6H),1.36(dd, J ═ 20.2,8.2Hz,2H), 1.28-1.00 (m,8H), and the detailed map is shown in fig. 10.
From the above examples, it can be seen that the preparation method of the present invention can efficiently synthesize the aromatic phosphine oxide compound, and has the advantages of simple and efficient reaction process, mild conditions, high yield, wide raw material sources, low toxicity, environmental friendliness, and economy.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
Claims (5)
1. The preparation method of the aromatic phosphine oxide compound is characterized by comprising the following steps:
adding a P (O) -H compound, a fluoro aromatic compound and an alkali reagent into an organic solvent under an inert atmosphere, mixing, stirring and reacting at 60-140 ℃ for 10-24H, and cooling to obtain a mixed solution;
washing and extracting the mixed solution to obtain an organic phase, drying and distilling the organic phase, and then carrying out column chromatography to obtain an aromatic phosphine oxide compound;
the P (O) -H compound is diphenyl phosphine oxide, bis (4-methylphenyl) phosphine oxide, bis (4-methoxyphenyl) phosphine oxide, di-n-butyl phosphine oxide, dicyclohexylphosphine oxide;
the fluorinated aromatic hydrocarbon compound is 1-fluoronaphthalene, 2-fluoropyridine, 3-fluoropyridine, 4-fluorobenzonitrile, 4-fluoro-benzotrifluoride and 6-fluoro-2-methylquinoline;
the structural formula of the aromatic phosphine oxide compound is as follows:
wherein R is trifluoromethyl, cyano or aryl and is one of naphthyl, pyridyl and substituted quinolyl; r2Or R3Is one of phenyl, 4-methylphenyl, 4-methoxyphenyl, n-butyl or cyclohexyl.
2. The method for producing an aromatic phosphine oxide compound according to claim 1, wherein the molar ratio of the P (O) -H compound, the fluorinated aromatic compound and the alkali agent is 1:1 to 2:1 to 3.
3. The method for producing an aromatic phosphine oxide compound according to claim 1, wherein the alkali agent is one or both of sodium t-butoxide and potassium t-butoxide.
4. The method for producing an aromatic phosphine oxide compound according to claim 1, wherein the organic solvent is one or more of toluene, N-dimethylformamide, 1, 4-dioxane and tetrahydrofuran.
5. The method for preparing an aromatic phosphine oxide compound according to claim 1, wherein the step of washing and extracting the mixed solution to obtain an organic phase, drying and distilling the organic phase, and then performing column chromatography to obtain the aromatic phosphine oxide compound specifically comprises:
washing the mixed solution with water, removing water-soluble impurities, and adding an extracting agent for extraction to obtain an organic phase;
adding a drying agent into the organic phase for drying, and removing the solvent by reduced pressure distillation to obtain a crude product of the aromatic phosphine oxide compound;
and (3) separating the crude product of the aromatic phosphine oxide compound by column chromatography to obtain the aromatic phosphine oxide compound.
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| CN109369716A (en) * | 2018-09-14 | 2019-02-22 | 广东工业大学 | A kind of aryl oxidized phosphine compound and its synthetic method and application |
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| CN109369716A (en) * | 2018-09-14 | 2019-02-22 | 广东工业大学 | A kind of aryl oxidized phosphine compound and its synthetic method and application |
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