CN110734387B - Axial chiral biphenyl ring-chain isomerization compound and preparation method and application thereof - Google Patents
Axial chiral biphenyl ring-chain isomerization compound and preparation method and application thereof Download PDFInfo
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- CN110734387B CN110734387B CN201810805727.5A CN201810805727A CN110734387B CN 110734387 B CN110734387 B CN 110734387B CN 201810805727 A CN201810805727 A CN 201810805727A CN 110734387 B CN110734387 B CN 110734387B
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- biphenyl
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 85
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 title claims abstract description 61
- 235000010290 biphenyl Nutrition 0.000 title claims abstract description 42
- 239000004305 biphenyl Substances 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 238000006317 isomerization reaction Methods 0.000 title claims description 4
- -1 biphenyl compound Chemical class 0.000 claims abstract description 112
- 230000003287 optical effect Effects 0.000 claims abstract description 51
- 238000000034 method Methods 0.000 claims abstract description 25
- 150000001412 amines Chemical class 0.000 claims abstract description 11
- 150000003335 secondary amines Chemical class 0.000 claims abstract description 9
- 150000003141 primary amines Chemical class 0.000 claims abstract description 8
- 238000002983 circular dichroism Methods 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 34
- MXLMTQWGSQIYOW-UHFFFAOYSA-N 3-methyl-2-butanol Chemical compound CC(C)C(C)O MXLMTQWGSQIYOW-UHFFFAOYSA-N 0.000 claims description 19
- 239000002904 solvent Substances 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000002808 molecular sieve Substances 0.000 claims description 11
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical group [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 11
- CHPRFKYDQRKRRK-UHFFFAOYSA-N 2-(methoxymethyl)pyrrolidine Chemical compound COCC1CCCN1 CHPRFKYDQRKRRK-UHFFFAOYSA-N 0.000 claims description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical group CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 9
- 239000012024 dehydrating agents Substances 0.000 claims description 8
- 230000035484 reaction time Effects 0.000 claims description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 7
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- 150000007514 bases Chemical class 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 230000002378 acidificating effect Effects 0.000 claims description 5
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical group [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 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
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 238000011088 calibration curve Methods 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 3
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 claims description 2
- WAPNOHKVXSQRPX-UHFFFAOYSA-N 1-phenylethanol Chemical compound CC(O)C1=CC=CC=C1 WAPNOHKVXSQRPX-UHFFFAOYSA-N 0.000 claims description 2
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 claims description 2
- ITATYELQCJRCCK-UHFFFAOYSA-N Mandelic Acid, Methyl Ester Chemical compound COC(=O)C(O)C1=CC=CC=C1 ITATYELQCJRCCK-UHFFFAOYSA-N 0.000 claims description 2
- XPNGNIFUDRPBFJ-UHFFFAOYSA-N alpha-methylbenzylalcohol Natural products CC1=CC=CC=C1CO XPNGNIFUDRPBFJ-UHFFFAOYSA-N 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 150000008282 halocarbons Chemical group 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 239000011261 inert gas Substances 0.000 claims description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 2
- 229940041616 menthol Drugs 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- DFOXKPDFWGNLJU-UHFFFAOYSA-N pinacolyl alcohol Chemical compound CC(O)C(C)(C)C DFOXKPDFWGNLJU-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 239000011698 potassium fluoride Substances 0.000 claims description 2
- 235000003270 potassium fluoride Nutrition 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims 3
- 238000004519 manufacturing process Methods 0.000 claims 1
- 150000001298 alcohols Chemical class 0.000 abstract description 5
- 238000001514 detection method Methods 0.000 abstract description 4
- 238000000746 purification Methods 0.000 abstract description 4
- 238000000926 separation method Methods 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 3
- 238000000691 measurement method Methods 0.000 abstract description 2
- 238000003556 assay Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- 125000004432 carbon atom Chemical group C* 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 9
- 125000002619 bicyclic group Chemical group 0.000 description 9
- 125000000623 heterocyclic group Chemical group 0.000 description 9
- 150000002430 hydrocarbons Chemical group 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 125000002950 monocyclic group Chemical group 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 239000004215 Carbon black (E152) Substances 0.000 description 6
- 125000001072 heteroaryl group Chemical group 0.000 description 6
- 229930195733 hydrocarbon Natural products 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
- 239000012069 chiral reagent Substances 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- 125000006651 (C3-C20) cycloalkyl group Chemical group 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 125000005605 benzo group Chemical group 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 description 2
- 125000006714 (C3-C10) heterocyclyl group Chemical group 0.000 description 2
- 125000006708 (C5-C14) heteroaryl group Chemical group 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 125000006218 1-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000005916 2-methylpentyl group Chemical group 0.000 description 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 2
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 description 2
- 125000005865 C2-C10alkynyl group Chemical group 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 238000004896 high resolution mass spectrometry Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 125000006413 ring segment Chemical group 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- DGUWACLYDSWXRZ-UHFFFAOYSA-N (2-formylphenyl)boronic acid Chemical compound OB(O)C1=CC=CC=C1C=O DGUWACLYDSWXRZ-UHFFFAOYSA-N 0.000 description 1
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- FKVCJQNPXXXZIE-UHFFFAOYSA-N 2-bromo-n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC=C1Br FKVCJQNPXXXZIE-UHFFFAOYSA-N 0.000 description 1
- XRXMNWGCKISMOH-UHFFFAOYSA-N 2-bromobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Br XRXMNWGCKISMOH-UHFFFAOYSA-N 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
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- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
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- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
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- 125000005915 C6-C14 aryl group Chemical group 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
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- 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 1
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- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 238000000711 polarimetry Methods 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000005551 pyridylene group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000004808 supercritical fluid chromatography Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005329 tetralinyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000005556 thienylene group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000005455 trithianyl group Chemical group 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/19—Dichroism
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- G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N24/00—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects
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Abstract
本发明属于手性化合物识别和纯度测定技术领域，具体涉及轴手性联苯环‑链异构化合物及其制备方法与应用。本发明设计合成了轴手性联苯化合物，所述化合物具有环‑链互变异构体。本发明的制备方法无需复杂的分离提纯、操作简单、产物易纯化、重现性好，且产品的化学性质稳定。而且，本发明化合物在高通量手性醇、伯胺、仲胺的光学纯度检测方面有巨大的应用前景。此外，本发明测定手性醇、伯胺、仲胺光学纯度的方法克服了常规测量方法的缺点，具有测试精度高、耗时短、成本低、易推广等优点。本发明提供了一种全新的可用于单官能团的手性醇、胺光学纯度的测定手段。并且，本发明测定方法的检出限低。
The invention belongs to the technical field of chiral compound identification and purity determination, and in particular relates to an axial chiral biphenyl ring-chain isomer compound and a preparation method and application thereof. The present invention designs and synthesizes an axial chiral biphenyl compound, and the compound has a ring-chain tautomer. The preparation method of the invention does not need complicated separation and purification, has simple operation, easy product purification, good reproducibility, and stable chemical properties of the product. Moreover, the compounds of the present invention have great application prospects in the optical purity detection of high-throughput chiral alcohols, primary amines and secondary amines. In addition, the method for measuring the optical purity of chiral alcohols, primary amines and secondary amines of the present invention overcomes the shortcomings of conventional measurement methods, and has the advantages of high test accuracy, short time consumption, low cost, easy popularization and the like. The present invention provides a new method for measuring the optical purity of monofunctional chiral alcohols and amines. Furthermore, the detection limit of the assay method of the present invention is low.
Description
Technical Field
The invention belongs to the technical field of chiral compound identification and purity determination, and particularly relates to an axial chiral biphenyl ring-chain isomerization compound and a preparation method and application thereof.
Background
In nature, the two enantiomers of a chiral compound are present in different amounts, with obvious differences in metabolic and pharmacological actions between them. In the field of organic synthesis, the degree of enantiomeric excess (e.e.%) in the product is a key issue for asymmetric synthesis. Therefore, the analysis of the content of enantiomers is of great significance in the fields of biomedicine and organic synthesis.
In the case of chiral compounds, in the absence of an external chiral environment, the two enantiomers have, in addition to optical activity, identical chemical and physical properties, showing identical melting points, solubilities, infrared spectra, nuclear magnetic resonance spectra, and also identical retention times on the chromatograms (gas and liquid). Researchers at home and abroad have established many methods for qualitatively or quantitatively analyzing the enantiomeric excess for many years, which mainly comprise means such as chromatography (including high performance liquid chromatography, gas chromatography and supercritical fluid chromatography), nuclear magnetic resonance analysis, spectrometry (including optical rotation and circular dichroism), and the like. The purpose of separation and analysis is achieved by means of a chiral stationary phase, a chiral reagent or a chiral mobile phase in the chromatography, the method is the most widely applied chiral analysis method with the best analysis effect at present, but the chromatography has the problems of longer analysis period, high required purity of the chiral reagent, high price of a chiral chromatographic column and the like, and the popularization and application of the chromatography are limited to a certain extent. Nmr methods, while capable of rapid analysis of molecular structure, do not give accurate results for compounds with excessive optical purity (e.g., e.e. > 95%). Polarimetry is most convenient and fast, but often requires large sample volumes, is greatly affected by external temperature and solvent changes, and is easily interfered by impurities. The Circular Dichroism (CD) method is established on the basis of different absorption capacities of left and right circularly polarized light, overcomes the defects of an optical rotation method, has higher sensitivity and selectivity, short analysis period, small external interference and low price, has important application in chiral identification and has obvious advantages in high-flux chiral identification.
The bifunctional chiral molecules, such as amino acid, diamine, amino alcohol and the like, can react with chiral reagents at multiple sites through abundant chelation to form diastereoisomer intermediate compounds, and further achieve the purpose of analyzing the content of enantiomers by utilizing different CD signals. For many monofunctional chiral alcohols and chiral amines (especially chiral secondary amines, which have greater steric hindrance), it is difficult to form diastereoisomers by reaction with chiral reagents, and analysis of their enantiomeric contents is therefore more challenging.
Disclosure of Invention
In order to improve the above problems, the present invention provides a compound represented by the following formula (a) or formula (B):
wherein X, Y, R are the same or different and independently represent H, F, Cl, Br, I, -NO2Unsubstituted or optionally substituted by one or more RaSubstituted of the following groups: c1-40Alkyl radical, C1-40Alkoxy radical, C3-20Cycloalkyl, 3-20 membered heterocyclyl, C6-20Aryl, 5-20 membered heteroaryl;
each RaIdentical or different, independently of one another, from the group-F, -Cl, -Br, -I, -OH, -SH, -CN, -NH2、＝O、-NO2、-NH2Unsubstituted or optionally substituted by one or more RnSubstituted of the following groups: c1-40Alkyl radical, C1-40Alkyloxy, C1-40Alkylthio radical, C2-40Alkenyl radical, C2-40Alkenyloxy radical, C2-40Alkenylthio radical, C2-40Alkynyl, C2-40Alkynyloxy, C2-40Alkynylthio, C3-20Cycloalkyl radical, C3-20Cycloalkyl oxy, C3-20Cycloalkylthio, 3-20 membered heterocyclyl, 3-20 membered heterocyclyloxy, 3-20 membered heterocyclylthio, C6-20Aryl radical, C6-20Aryloxy radical, C6-20Arylthio, 5-20 membered heteroaryl, 5-20 membered heteroaryloxy, 5-20 membered heteroarylthio;
each RnIdentical or different, independently of one another, from the group consisting of H, -NH2、＝O、C1-40Alkyl radical, C2-40Alkenyl radical, C2-40Alkynyl, C3-20Cycloalkyl, 3-20 membered heterocyclyl, C6-20Aryl, 5-20 membered heteroaryl.
According to an embodiment of the invention, said X, Y, R are the same or different and are independently selected from H, C1-40An alkyl group. Example (b)E.g., X, Y is selected from H and R is selected from CH3、C2H5、C3H7Or C4H9。
According to an embodiment of the invention, the compounds of formula (a) and (B) are each an axial chiral biphenyl ring-chain isomer, in particular an axial chiral biphenyl ring-chain tautomer.
The invention also provides a preparation method of the compound shown in the formula (A) or the formula (B), which comprises the steps of reacting the compound shown in the formula (I) with the compound shown in the formula (II) to obtain the compound shown in the formula (A) or the formula (B);
wherein X, Y, R has the definitions described above.
According to the invention, the reaction can be carried out under an inert gas blanket, such as a nitrogen blanket;
the reaction may be carried out in the presence of a tetradentate palladium catalyst, which may be Pd (PPh)3)4；
The reaction may further be carried out in the presence of a base and/or fluoride; wherein the base may be a salt of an alkali metal, for example a carbonate of an alkali metal, such as Cs2CO3、K2CO3、Na2CO3、Li2CO3One or more of; the fluoride can be one or more of tetrabutylammonium fluoride, cesium fluoride and potassium fluoride;
the molar ratio of the compound of formula (I) to the compound of formula (II) may be 1 (1-3), preferably 1 (1.5-2.5), for example 1: 2;
the molar ratio of the catalyst to the compound of formula (I) may be (0.03-0.07):1, preferably (0.04-0.06):1, for example 0.05: 1;
the molar ratio of the base and/or fluoride to the compound of formula (I) may be (1-5) to 1, preferably (2-4) to 1, for example 3: 1;
the reaction may be carried out in a solvent, and the solvent for the reaction may be a mixed solvent of an ether solvent and water, for example, a mixed solvent of 1, 4-dioxane and water;
the temperature of the reaction may be from 25 to 100 ℃, preferably from 60 to 100 ℃, for example 80 ℃;
the reaction time may be 6 to 24 hours, preferably 18 to 24 hours.
According to the invention, the preparation method further comprises the following steps:
1) reacting the compound of the formula (III) with thionyl chloride to obtain a compound of a formula (IV);
2) compounds of formula (IV) and RNH2Reacting to obtain a compound shown in a formula (I);
wherein X, R has the definitions described above.
According to the present invention, in step 1),
the reaction time may be 4 to 8 hours, preferably 5 to 7 hours, for example 6 hours.
The reaction may be carried out under heating, for example under reflux.
According to the present invention, in step 2),
the reaction may be carried out with the addition of a base, which may be an inorganic base such as sodium carbonate;
the molar ratio of the compound of formula (IV) to the base may be 1 (1-5), preferably 1 (2-4), for example 1: 3;
the reaction time may be 1 to 3 hours, for example 2 hours.
The reaction may be carried out in a solvent, which may be a halogenated hydrocarbon solvent, such as dichloromethane.
The invention also provides application of the axial chiral biphenyl compound, and the axial chiral biphenyl compound can be used for measuring the optical purity of the chiral compound.
According to the invention, the chiral compound may be a chiral alcohol, a chiral amine;
according to the invention, the chiral amine may be a chiral primary or a chiral secondary amine; the chiral amine is for example selected from 1-phenylethylamine, chiral 2- (methoxymethyl) pyrrolidine.
According to the invention, the chiral alcohol may be a chiral compound containing hydroxyl groups, such as chiral 3, 3-dimethyl-2-butanol, 3-methyl-2-butanol, menthol, 1-phenylethanol, methyl mandelate.
The present invention also provides a method for determining optical purity of a chiral compound, using the above axial chiral biphenyl compound, the method comprising the steps of:
(1) preparing an axial chiral biphenyl compound solution;
(2) adding a series of chiral compound solutions with known optical purity into the axial chiral biphenyl compound solution prepared in the step (1) for reaction, detecting a signal of the obtained product through a Circular Dichroism (CD), and establishing a calibration curve, namely establishing a relation between the CD signal and the optical purity of the chiral compound;
(3) adding a chiral compound solution with unknown optical purity into the axial chiral biphenyl compound solution prepared in the step (1), reacting, detecting signals of the obtained product through a Circular Dichroism (CD), and determining the optical purity of the chiral compound solution based on the relation between the CD signals established in the step (2) and the optical purity of the chiral compound.
According to the present invention, in the step (1), the solution of the axial chiral biphenyl compound is preferably a solution prepared by dissolving the axial chiral biphenyl compound in a nitrile solvent, for example, a solution prepared by dissolving the axial chiral biphenyl compound in acetonitrile.
The concentration of the axial chiral biphenyl compound solution can be 17mmol/L to 29mmol/L, preferably 20mmol/L to 26mmol/L, such as 23 mmol/L.
According to the present invention, when the method is used for measuring the optical purity of a chiral alcohol, an acid catalyst and/or a dehydrating agent may be added to the solution of step (1);
the acidic catalyst is selected from methanesulfonic acid;
the mass ratio of the acidic catalyst to the axial chiral biphenyl compound may be (0.1-0.7) to 1, preferably (0.2-0.6) to 1, e.g. 0.375: 1;
the dehydrating agent is selected from molecular sieves.
The amount of the dehydrating solvent used in the present invention is not particularly limited, and for example, 1 to 5 molecular sieves, preferably 1 molecular sieve, can be used.
According to the present invention, when the method is used for measuring the optical purity of chiral amines, a dehydrating agent, and optionally a basic compound, may be added to the solution of step (1);
the dehydrating agent is selected from molecular sieves;
the amount of the dehydrating solvent used in the present invention is not particularly limited, and for example, 1 to 5 molecular sieves, preferably 1 molecular sieve, can be used.
The basic compound is selected from triethylamine.
The mass ratio of the basic compound to the axial chiral biphenyl compound may be (0-0.5):1, preferably (0-0.1):1, e.g. 0, 0.875: 1.
According to the invention, in step (2), the optical purity of the solution of chiral compound of known optical purity is selected, for example, from-100%, -66.67%, -33.33%, 0, 33.33%, 66.67%, 100%.
According to the invention, the axial chiral biphenyl compound reacted with the chiral compound may be a compound of formula (a) or a compound of formula (B), preferably a compound of formula (B);
the temperature of the reaction may be 0-60 ℃;
the reaction time may be 6-12 hours;
according to the invention, a linear relation graph of optical purity and CD intensity can be established by taking the CD intensity value at the position of a peak of 225nm-285nm, preferably the CD intensity value at the position of 245nm-265nm, such as the CD intensity values at the positions of 245nm, 260nm and 265 nm.
The invention has the advantages of
(1) The axial chiral biphenyl compound is designed and synthesized, and has a ring-chain tautomer, the preparation method of the invention does not need complicated separation and purification, is simple to operate, and has the advantages of easy product purification, good stability, good reproducibility and stable chemical properties of the product.
(2) The biphenyl axis chiral compound has excellent reactivity with chiral alcohol, primary amine and secondary amine with single functional group, and high conversion rate. The diastereoisomer formed after the reaction has stronger CD signal and is easy to detect. Has great application prospect in the aspect of optical purity detection of high-throughput chiral alcohol, primary amine and secondary amine.
(3) The method for determining the optical purity of the chiral alcohol, the primary amine and the secondary amine overcomes the defects of the conventional measuring methods (such as a chromatography method, a nuclear magnetic method and an optical rotation method), and has the advantages of high measuring precision, short time consumption, low cost, easiness in popularization and the like. The invention provides a brand-new measuring method for optical purity of chiral alcohol and amine with single functional group. Furthermore, the detection limit of the measurement method of the present invention is low, and the optical purity of chiral 3-methyl-2-butanol, 1-phenylethylamine and 2- (methoxymethyl) pyrrolidine can be measured with the compound of the present invention at a concentration of only 23 mM.
Definition and description of terms
Unless otherwise indicated, the definitions of radicals and terms set forth in the specification and claims of this application, including definitions thereof as examples, exemplary definitions, preferred definitions, definitions of particular compounds in the examples, and the like, may be combined with one another in any combination and permutation. The definitions of the groups and the structures of the compounds in such combinations and after the combination are within the scope of the present specification.
The term "C1-40Alkyl is understood to preferably mean a straight-chain or branched, saturated monovalent hydrocarbon radical having from 1 to 40 carbon atoms, preferably C1-10An alkyl group. "C1-10Alkyl "is understood to preferably mean a straight-chain or branched, saturated monovalent hydrocarbon radical having 1,2, 3,4, 5,6, 7, 8, 9 or 10 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 2-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2,1, 3-dimethylbutyl or 1, 2-dimethylbutyl, and the like, or isomers thereof. In particular, the radicals have 1,2, 3,4, 5,6 carbon atoms ("C)1-6Alkyl groups) such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, more particularly groups having 1,2 or 3 carbon atoms ("C)1-3Alkyl groups) such as methyl, ethyl, n-propyl or isopropyl.
The term "C2-40Alkenyl "is understood to preferably mean a straight-chain or branched monovalent hydrocarbon radical comprising one or more double bonds and having from 2 to 40 carbon atoms, preferably" C2-10Alkenyl ". "C2-10Alkenyl "is understood to preferably mean a straight-chain or branched, monovalent hydrocarbon radical which contains one or more double bonds and has 2,3, 4,5, 6, 7, 8, 9 or 10 carbon atoms, in particular 2 or 3 carbon atoms (" C2-3Alkenyl "), it being understood that in the case where the alkenyl group comprises more than one double bond, the double bonds may be separated from each other or conjugated. The alkenyl group is, for example, vinyl, allyl, (E) -2-methylvinyl, (Z) -2-methylvinyl, (E) -but-2-enyl, (Z) -but-2-enyl, (E) -but-1-enyl, (Z) -but-1-enyl, pent-4-enyl, (E) -pent-3-enyl, (Z) -pent-3-enyl, (E) -pent-2-enyl, (Z) -pent-2-enyl, (E) -pent-1-enyl, (Z) -pent-1-enyl, hex-5-enyl, (E) -hex-4-enyl, (Z) -hex-4-enyl, m-n-2-enyl, m-n-1-enyl, m-n-E-4-enyl, m-n-2-, (E) -hex-3-enyl, (Z) -hex-3-enyl, (E) -hex-2-enyl, (Z) -hex-2-enyl, (E) -hex-1-enyl, (Z) -hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E) -1-methylprop-1-enyl, (Z) -1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E) -2-methylbut-2-enyl, (Z) -2-methylbut-2-enyl, (E) -1-methylbut-2-enyl, (Z) -1-methylbut-2-enyl, (E) -3-methylbut-1-enyl, (Z) -3-methylbut-1-enyl, (E) -2-methylbut-1-enyl, (Z) -2-methylbut-1-enyl, (E) -1-methylbut-1-enyl, (Z) -1-methylbut-1-enyl, 1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl group and 1-isopropylvinyl group.
The term "C2-40Alkynyl "is understood to mean a straight-chain or branched monovalent hydrocarbon radical comprising one or more triple bonds and having from 2 to 40 carbon atoms, preferably" C2-C10Alkynyl ". The term "C2-C10Alkynyl "is understood as preferably meaning a straight-chain or branched, monovalent hydrocarbon radical which contains one or more triple bonds and has 2,3, 4,5, 6, 7, 8, 9 or 10 carbon atoms, in particular 2 or 3 carbon atoms (" C2-C3-alkynyl "). The alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, prop-2-ynyl, but-3-methylbut-1-ynyl, and so-1-ethylprop, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2-dimethylbut-3-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-1-ynyl, 3-methylpent-1-, 1, 1-dimethylbut-3-ynyl, 1-dimethylbut-2-ynyl or 3, 3-dimethylbut-1-ynyl. In particular, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.
The term "C3-20Cycloalkyl is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 20 carbon atoms, preferably "C3-10Cycloalkyl groups ". The term "C3-10Cycloalkyl "is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3,4, 5,6, 7, 8, 9 or 10 carbon atoms. Said C is3-10Cycloalkyl groups may be monocyclic hydrocarbon groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or bicyclic hydrocarbon groups such as decalin rings.
The term "3-20 membered heterocyclyl" means a saturated monovalent monocyclic or bicyclic hydrocarbon ring comprising 1-5 heteroatoms independently selected from N, O and S, preferably "3-10 membered heterocyclyl". The term "3-10 membered heterocyclyl" means a saturated monovalent monocyclic or bicyclic hydrocarbon ring comprising 1-5, preferably 1-3 heteroatoms selected from N, O and S. The heterocyclic group may be attached to the rest of the molecule through any of the carbon atoms or nitrogen atom (if present). In particular, the heterocyclic group may include, but is not limited to: 4-membered rings such as azetidinyl, oxetanyl; 5-membered rings such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl; or a 7-membered ring such as diazepanyl. Optionally, the heterocyclic group may be benzo-fused. The heterocyclyl group may be bicyclic, for example but not limited to a 5,5 membered ring, such as a hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl ring, or a 5,6 membered bicyclic ring, such as a hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -yl ring. The nitrogen atom containing ring may be partially unsaturated, i.e., it may contain one or more double bonds, such as, but not limited to, 2, 5-dihydro-1H-pyrrolyl, 4H- [1,3,4] thiadiazinyl, 4, 5-dihydrooxazolyl, or 4H- [1,4] thiazinyl, or it may be benzo-fused, such as, but not limited to, dihydroisoquinolinyl. According to the invention, the heterocyclic radical is non-aromatic.
The term "C6-20Aryl "is understood to preferably mean a mono-, bi-or tricyclic hydrocarbon ring having a monovalent or partially aromatic character with 6 to 20 carbon atoms, preferably" C6-14Aryl ". The term "C6-14Aryl "is to be understood as preferably meaning a mono-, bi-or tricyclic hydrocarbon ring having a monovalent or partially aromatic character with 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms (" C6-14Aryl group "), in particular a ring having 6 carbon atoms (" C6Aryl "), such as phenyl; or biphenyl, or is a ring having 9 carbon atoms ("C9Aryl), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C10Aryl radicals), such as tetralinyl, dihydronaphthyl or naphthyl, or rings having 13 carbon atoms ("C13Aryl radicals "), examplesSuch as fluorenyl, or a ring having 14 carbon atoms ("C)14Aryl), such as anthracenyl.
The term "5-20 membered heteroaryl" is understood to include such monovalent monocyclic, bicyclic or tricyclic aromatic ring systems: having 5 to 20 ring atoms and comprising 1 to 5 heteroatoms independently selected from N, O and S, such as "5-14 membered heteroaryl". The term "5-14 membered heteroaryl" is understood to include such monovalent monocyclic, bicyclic or tricyclic aromatic ring systems: which has 5,6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and which comprises 1 to 5, preferably 1 to 3, heteroatoms each independently selected from N, O and S and, in addition, can be benzo-fused in each case. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl and the like and their benzo derivatives, such as benzofuryl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl, and the like; or azocinyl, indolizinyl, purinyl and the like and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and the like.
Unless otherwise indicated, heterocyclyl, heteroaryl or heteroarylene include all possible isomeric forms thereof, e.g., positional isomers thereof. Thus, for some illustrative, non-limiting examples, pyridyl or pyridinylene includes pyridin-2-yl, pyridinylene-2-yl, pyridin-3-yl, pyridinylene-3-yl, pyridin-4-yl, and pyridinylene-4-yl; thienyl or thienylene includes thien-2-yl, thien-3-yl and thien-3-yl.
Drawings
FIG. 1 is a schematic diagram of the synthesis of a biphenyl axis chiral cyclo-chain isomeric compound of example 1.
Fig. 2 is a circular dichroism graph of biphenyl axis chiral cyclo-chain isomeric compound (23mmol/L) after reaction with 3-methyl-2-butanol of different optical purity (e.e.%).
Fig. 3 is a circular dichroism graph of biphenyl axis chiral cyclo-chain isomeric compound (23mmol/L) after reaction with 1-phenylethylamine of different optical purity (e.e.%).
Fig. 4 is a circular dichroism spectrum of biphenyl axis chiral cyclo-chain isomeric compound (23mmol/L) after reaction with 2- (methoxymethyl) pyrrolidine of different optical purity (e.e.%).
Fig. 5 is a calibration curve of biphenyl axis chiral cyclo-chain isomeric compound (23mmol/L) against chiral 3-methyl-2-butanol, 1-phenylethylamine, 2- (methoxymethyl) pyrrolidine of different optical purity (e.e.%).
Detailed Description
The present invention will be described in further detail with reference to specific examples. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
Instruments and reagents:1H-NMR was measured using a 400MHz Bruker Biospin amplitude type III NMR spectrometer; circular dichroism was measured using a French Bio-Logic model MOS-450 circular dichroism spectrometer (1cm quartz cuvette); chiral 3-methyl-2-butanol, 1-phenylethylamine, and 2- (methoxymethyl) pyrrolidine were purchased from Alfa Aesar for calibration, and all other reagents were commercially available analytical grade reagents.
Example 1
Step 1:
synthesis of (2)
With R ═ CH3For example, 80-100mL of thionyl chloride was added to a 250mL round bottom flask containing o-bromobenzoic acid (6g,30mmol), and the reaction was terminated after 6 hours of reflux, after which thionyl chloride was removed to give a white solid with a pungent odor. 2.19g (10mmol) of this white solid was dissolved in 10mL of dichloromethane, and slowly added dropwise with stirring at 0 deg.CTo 40mL of dichloromethane containing 5-10mL of aqueous methylamine (40%), sodium carbonate (3.18g,30 mmol). After 2 hours of reaction, insoluble matter was filtered off, and the filter cake was thoroughly washed with 120mL of dichloromethane. The collected dichloromethane was washed 3 times with saturated aqueous sodium carbonate solution (40 mL. times.3), and the organic phase was separated and dried over anhydrous sodium sulfate. After filtration, methylene chloride was spin-dried to give 2.1 g of a white solid with a yield of 95% and a purity of 90%.
In the same way, R ═ C can be obtained2H5,C3H7,C4H9And the specific characterization data of the products are as follows:
R＝CH3，1H NMR(400MHz,CDCl3)δ＝7.59(1H,Ar H),7.53(1H,Ar H),7.36(1H,Ar H),7.28(1H,Ar H),6.08(br s,1H,NH),3.02(d,J＝4.8Hz,3H,CH3).
R＝C2H5the yield is 90 percent, and the purity is 95 percent.1H NMR(400MHz,CDCl3)δ＝7.61(1H,Ar H),7.54(1H,Ar H),7.37(1H,Ar H),7.28(1H,Ar H),5.99(br s,1H,NH),3.50-3.54(m,2H,CH2),1.28(t,3H,CH3).
R＝C3H7The yield is 92% and the purity is 95%.1H NMR(400MHz,CDCl3)δ＝7.59(dd,J＝8,1.2Hz,1H,Ar H),7.53(dd,J＝7.6,1.6Hz,1H,Ar H),7.37(ddd,J＝14.8,7.2,0.8Hz,1H,Ar H),7.29(ddd,J＝15.2,7.6,0.8Hz,1H,Ar H),6.05(br s,1H,NH),3.41-3.45(m,2H,CH2),1.65-1.69(m,2H,CH2),1.02(t,3H,CH3).
R＝C4H9The yield is 90 percent, and the purity is 95 percent.1H NMR(400MHz,CDCl3)δ＝7.60(dd,J＝8,0.8Hz,1H,Ar H),7.55(dd,J＝7.2,0.8Hz,1H,Ar H),7.37(ddd,J＝15.2,7.6,0.8Hz,1H,Ar H),7.28(ddd,J＝15.2,7.6,1.2Hz,1H,Ar H),5.98(br s,1H,NH),3.47-3.53(m,2H,CH2),1.62-1.65(m,2H,CH2),1.44-1.47(m,2H,CH2),0.99(t,3H,CH3).
Step 2:
synthesis of (2)
With R ═ CH3For example, the product obtained in step 1, 2-bromo-N-methylbenzamide (0.214g,1mmol), Pd (PPh) was added under nitrogen3)4(60mg,0.05mmol), CsF (0.456g,3mmol) was dissolved in a mixture of 15mL1, 4-dioxane and 8mL water, a solution of 2-formylphenylboronic acid (0.3g,2mmol) in 10mL 1, 4-dioxane was slowly added, the reaction was terminated at 80 ℃ for 18-24 hours, after the reaction solution was cooled to room temperature, the mixture was extracted twice with ethyl acetate (40 mL. times.2), the organic phase was collected, washed twice with saturated brine (40 mL. times.2) and dried over anhydrous sodium sulfate. White solid was obtained by flash column separation and recrystallized from acetonitrile to obtain 0.2g of white crystals with a yield of 83%. The presence of tautomeric compounds can be determined by nuclear magnetic data.
In the same way, R ═ C can be obtained2H5,C3H7,C4H9And the specific characterization data of the products are as follows:
R＝CH3，1H NMR(400MHz,CDCl3)δ＝7.50-7.60(m,12.48H,Ar H),5.83(d,J＝5.2Hz,1H),5.80(d,0.6H,J＝4Hz),5.11(d,J＝5.2Hz,1H),4.25(d,J＝4Hz,0.6H),3.22(s,1.8H),2.91(s,3H).
HR-MS:calcd for[M+H+]240.1025,found 240.1019.
calcd for[M+Na+]262.0844,found 262.0840.
R＝C2H5the yield is 80 percent, and the purity is 97 percent.1H NMR(400MHz,CDCl3)δ＝7.58-7.66(m,18.24H,Ar H),5.86(d,J＝4Hz,1.28H),5.80(d,J＝5.6Hz,1H),5.10(d,J＝5.6Hz,1H),4.11(d,J＝1.28Hz,4H),3.64(m,4.56H),1.16(t,J＝7.2Hz,3.84H),1.07(t,J＝7.2Hz,3H).
HR-MS:calcd for[M+Na+]276.1000,found 276.0997.
R＝C3H7The yield is 85 percent, and the purity is 95 percent.1H NMR(400MHz,CDCl3)δ＝7.50-7.62(m,19.76H,Ar H),5.84(d,J＝4.4Hz,1.47H),5.79(d,J＝5.6Hz,1H),5.15(d,J＝5.6Hz,1H),4.16(d,J＝4.4Hz,1.52H),3.69-3.75(m,1.47H),3.51-3.56(m,2.47H),3.38-3.42(m,1H),1.51-1.57(m,4.94H),0.84(t,J＝7.2Hz,4.41H),0.77(t,J＝7.2Hz,3H).
R＝C4H9The yield is 90 percent, and the purity is 95 percent.1H NMR(400MHz,CDCl3)δ＝7.55-7.66(m,20.21H,Ar H),5.84(d,J＝4.4Hz,1.52H),5.81(d,J＝6Hz,1H),5.01(d,J＝6Hz,1H),4.06(d,J＝4.4Hz,1.52H),3.72-3.77(m,1.52H),3.51-3.58(m,2.52H),3.42-3.47(m,1H),1.51-1.58(m,5.04H),1.21-1.28(m,5.04H),0.85-0.91(m,7.56H).
Example 2 determination of enantiomeric excess of chiral alcohol
The compound obtained in example 1 (R ═ CH) was synthesized using chiral 3-methyl-2-butanol as an example3) Dissolving 4mg in 0.7mL acetonitrile solution to prepare seven parts of solution with the concentration of 23mmol/L, adding 1.5mg of methanesulfonic acid and 1 particle molecular sieve into each part, then seven groups of 3-methyl-2-butanol enantiomer mixtures with known optical purities of-100%, -66.67%, -33.33%, 0, 33.33%, 66.67%, 100% were added, and after 10 hours of reaction with stirring at 20 ℃, 17. mu.L of each solution was taken out and dissolved in 3mL of acetonitrile, testing the CD signal, taking the CD intensity value at the position of 260nm of the wave peak, establishing a linear relation graph of optical purity and CD intensity, on the basis, five groups of 3-methyl-2-butanol samples with unknown optical purity are measured, and the results are shown in the following table 1, and the results are well matched with the linear fitting curve obtained before, which indicates that the chiral alcohol enantiomer excess measurement is very accurate.
TABLE 1 five groups of 3-methyl-2-butanol samples of unknown optical purity and absolute error table read from the linear fitting curve of FIG. 5
Example 3 determination of enantiomeric excess of chiral primary amine
The compound obtained in example 1 (R ═ CH) was exemplified by chiral 1-phenylethylamine3) Dissolving 4mg in 0.7mL acetonitrile solution to prepare seven parts of solution with the concentration of 23mmol/L, adding 3.5mg of triethylamine and 1 particle molecular sieve into each part, then adding seven groups of known optical purities of-100%, -66.67%,33.33 percent, 0, 33.33 percent, 66.67 percent and 100 percent of 1-phenylethylamine enantiomer mixture is stirred and reacted for 9 hours at 34 ℃, 17 mu L of solution is taken out each time and dissolved in 3mL of acetonitrile, CD signals are tested, CD intensity values at the positions of peaks 245nm are taken, a linear relation graph of optical purity and CD intensity is established, on the basis, five groups of 1-phenylethylamine samples with unknown optical purity are measured, and results are well matched with linear fitting curves obtained before, so that the enantiomeric excess measurement of the chiral primary amine is very accurate.
Example 4 determination of enantiomeric excess of chiral secondary amine
The compound obtained in example 1 (R ═ CH) was synthesized using chiral 2- (methoxymethyl) pyrrolidine as an example3) Dissolving 4mg in 0.7mL acetonitrile solution to prepare seven parts of solution with the concentration of 23mmol/L, adding 1 particle molecular sieve into each part, then seven groups of 2- (methoxymethyl) pyrrolidine enantiomer mixtures of known optical purities of-100%, -66.67%, -33.33%, 0, 33.33%, 66.67%, 100% were added, and after stirring the reaction at 53 ℃ for 9 hours, 17. mu.L of each solution was taken out and dissolved in 3mL of acetonitrile, testing the CD signal, taking the CD intensity value at the 265nm peak position to establish a linear relation graph of optical purity and CD intensity, on the basis, five groups of 2- (methoxymethyl) pyrrolidine samples with unknown optical purity are determined, and the results are well matched with the linear fitting curve obtained before, so that the enantiomeric excess determination of the 2- (methoxymethyl) pyrrolidine is very accurate.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. An axial chiral biphenyl ring-chain isomerization compound, which is characterized in that the structure of the compound is shown as the following formula (A) or formula (B):
wherein X, Y are the same or different and are independently selected from H, C1-6An alkyl group;
r is selected from CH3、C2H5Or C3H7；
The compound of formula (A) and the compound of formula (B) are each an axial chiral biphenyl ring-chain tautomer.
2. The process for preparing an axial chiral biphenyl cyclo-chain isomer compound of claim 1, which comprises reacting a compound of formula (I) with a compound of formula (II) to obtain a compound of formula (a) or (B);
wherein X, Y, R has the definition of claim 1.
3. The preparation method according to claim 2, wherein the reaction is carried out under an inert gas atmosphere;
the reaction is carried out in the presence of a tetradentate palladium catalyst, which is Pd (PPh)3)4；
The reaction is carried out in the presence of a base and/or a fluoride; wherein the base is an alkali metal salt, and the alkali metal salt is Cs2CO3、K2CO3、Na2CO3、Li2CO3One or more of; the fluoride is one or more of tetrabutylammonium fluoride, cesium fluoride and potassium fluoride;
the molar ratio of the compound of the formula (I) to the compound of the formula (II) is 1 (1-3);
the molar ratio of the catalyst to the compound of formula (I) is (0.03-0.07): 1;
the molar ratio of the base and/or fluoride to the compound of formula (I) is (1-5): 1;
the reaction is carried out in a solvent, and the solvent for the reaction is a mixed solvent of an ether solvent and water;
the reaction temperature is 25-100 ℃;
the reaction time is 6-24 hours.
4. The method for preparing according to claim 2 or 3, characterized in that it comprises the following steps:
1) reacting the compound of the formula (III) with thionyl chloride to obtain a compound of a formula (IV);
2) compounds of formula (IV) and RNH2Reacting to obtain a compound shown in a formula (I);
wherein X, R has the definition of claim 1.
5. The method according to claim 4, wherein, in step 1),
the reaction time is 4-8 hours;
the reaction may be carried out under heating;
in the step 2), the step (c) is carried out,
adding alkali into the reaction, wherein the alkali is inorganic alkali;
the molar ratio of the compound shown in the formula (IV) to the base is 1 (1-5);
the reaction time is 1-3 hours;
the reaction is carried out in a solvent, and the solvent is a halogenated hydrocarbon solvent.
6. The use of the axial chiral biphenyl cyclo-chain isomer compound according to claim 1, wherein the axial chiral biphenyl cyclo-chain isomer compound is used for measuring the optical purity of the chiral compound.
7. Use according to claim 6, wherein the chiral compound is a chiral alcohol, a chiral amine;
the chiral amine is chiral primary amine or chiral secondary amine;
the chiral alcohol is a chiral compound containing hydroxyl.
8. Use according to claim 6 or 7, characterized in that the chiral amine is 1-phenylethylamine, chiral 2- (methoxymethyl) pyrrolidine;
the chiral alcohol is chiral 3, 3-dimethyl-2-butanol, 3-methyl-2-butanol, menthol, 1-phenyl ethanol and methyl mandelate.
9. A method for measuring optical purity of a chiral compound, wherein the method uses the axial chiral biphenyl cyclo-chain isomeric compound of claim 1, the method comprising the steps of:
(1) preparing an axial chiral biphenyl compound solution;
(2) adding a series of chiral compound solutions with known optical purity into the axial chiral biphenyl compound solution prepared in the step (1) for reaction, detecting a signal of the obtained product through a Circular Dichroism (CD), and establishing a calibration curve, namely establishing a relation between the CD signal and the optical purity of the chiral compound;
(3) adding a chiral compound solution with unknown optical purity into the axial chiral biphenyl compound solution prepared in the step (1), reacting, detecting signals of the obtained product through a Circular Dichroism (CD), and determining the optical purity of the chiral compound solution based on the relation between the CD signals established in the step (2) and the optical purity of the chiral compound.
10. The method for measuring optical purity of a chiral compound according to claim 9, wherein in the step (1), the solution of the axial chiral biphenyl compound is a solution prepared by dissolving the axial chiral biphenyl compound in a nitrile solvent;
the concentration of the axial chiral biphenyl compound solution is 17 mmol/L-29 mmol/L;
when the method is used for determining the optical purity of chiral alcohol, adding an acidic catalyst and/or a dehydrating agent to the solution of the step (1);
the acidic catalyst is selected from methanesulfonic acid;
the mass ratio of the acidic catalyst to the axial chiral biphenyl compound is (0.1-0.7) to 1;
the dehydrating agent is selected from molecular sieves;
when the method is used for determining the optical purity of a chiral amine, adding a dehydrating agent, and optionally a basic compound, to the solution of step (1);
the dehydrating agent is selected from molecular sieves;
the basic compound is selected from triethylamine;
the mass ratio of the basic compound to the axial chiral biphenyl compound is (0-0.5) to 1;
in the step (2), the optical purity of the chiral compound solution with known optical purity is selected from-100%, -66.67%, -33.33%, 0, 33.33%, 66.67%, 100%;
the reaction temperature is 0-60 ℃;
the reaction time is 6-12 hours;
and taking the CD intensity value with the peak at 225nm-285nm to establish a linear relation graph of the optical purity and the CD intensity.
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