CN109748883B - Process for the preparation of chiral beta-amino derivatives - Google Patents
Process for the preparation of chiral beta-amino derivatives Download PDFInfo
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- CN109748883B CN109748883B CN201711101603.0A CN201711101603A CN109748883B CN 109748883 B CN109748883 B CN 109748883B CN 201711101603 A CN201711101603 A CN 201711101603A CN 109748883 B CN109748883 B CN 109748883B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 34
- 238000000034 method Methods 0.000 title claims description 39
- 230000008569 process Effects 0.000 title description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 104
- -1 azetidine quaternary ammonium salt Chemical class 0.000 claims abstract description 54
- 239000003054 catalyst Substances 0.000 claims abstract description 34
- 239000003960 organic solvent Substances 0.000 claims abstract description 29
- 238000007142 ring opening reaction Methods 0.000 claims abstract description 18
- 239000012434 nucleophilic reagent Substances 0.000 claims abstract description 12
- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 60
- 150000001875 compounds Chemical class 0.000 claims description 48
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 29
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 14
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 11
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 claims description 8
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- MNCMBBIFTVWHIP-UHFFFAOYSA-N 1-anthracen-9-yl-2,2,2-trifluoroethanone Chemical group C1=CC=C2C(C(=O)C(F)(F)F)=C(C=CC=C3)C3=CC2=C1 MNCMBBIFTVWHIP-UHFFFAOYSA-N 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 238000007254 oxidation reaction Methods 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 4
- 150000001555 benzenes Chemical group 0.000 claims description 4
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical group [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- FEMRXDWBWXQOGV-UHFFFAOYSA-N potassium amide Chemical compound [NH2-].[K+] FEMRXDWBWXQOGV-UHFFFAOYSA-N 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 2
- 229910000396 dipotassium phosphate Inorganic materials 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 2
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 229930192474 thiophene Natural products 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 2
- 229910000404 tripotassium phosphate Inorganic materials 0.000 claims description 2
- 229910000406 trisodium phosphate Inorganic materials 0.000 claims description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims 2
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 abstract description 66
- 229910000147 aluminium phosphate Inorganic materials 0.000 abstract description 33
- 238000005342 ion exchange Methods 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 229910019142 PO4 Inorganic materials 0.000 abstract description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 abstract description 2
- 239000010452 phosphate Substances 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 128
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 119
- 238000005481 NMR spectroscopy Methods 0.000 description 85
- 230000003287 optical effect Effects 0.000 description 83
- 238000004458 analytical method Methods 0.000 description 58
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- 238000001228 spectrum Methods 0.000 description 55
- 238000001819 mass spectrum Methods 0.000 description 46
- 238000004896 high resolution mass spectrometry Methods 0.000 description 41
- 239000006260 foam Substances 0.000 description 35
- 238000012360 testing method Methods 0.000 description 30
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 29
- 238000005160 1H NMR spectroscopy Methods 0.000 description 29
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 29
- 239000002585 base Substances 0.000 description 29
- 229910052799 carbon Inorganic materials 0.000 description 29
- 238000000921 elemental analysis Methods 0.000 description 29
- 229910052739 hydrogen Inorganic materials 0.000 description 29
- 239000001257 hydrogen Substances 0.000 description 29
- 238000002329 infrared spectrum Methods 0.000 description 29
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 28
- 230000014759 maintenance of location Effects 0.000 description 28
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- 239000002994 raw material Substances 0.000 description 27
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 26
- YXIWHUQXZSMYRE-UHFFFAOYSA-N 1,3-benzothiazole-2-thiol Chemical compound C1=CC=C2SC(S)=NC2=C1 YXIWHUQXZSMYRE-UHFFFAOYSA-N 0.000 description 25
- 238000004566 IR spectroscopy Methods 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 239000000243 solution Substances 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 150000001450 anions Chemical group 0.000 description 8
- 238000006555 catalytic reaction Methods 0.000 description 8
- 239000000376 reactant Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 125000003003 spiro group Chemical group 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 238000004293 19F NMR spectroscopy Methods 0.000 description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 3
- 238000003556 assay Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000007805 chemical reaction reactant Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 229910017053 inorganic salt Inorganic materials 0.000 description 2
- 239000012263 liquid product Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012038 nucleophile Substances 0.000 description 2
- 230000000269 nucleophilic effect Effects 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- QXTIBZLKQPJVII-UHFFFAOYSA-N triethylsilicon Chemical compound CC[Si](CC)CC QXTIBZLKQPJVII-UHFFFAOYSA-N 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Substances CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- NKYDKCVZNMNZCM-UHFFFAOYSA-N 5-chloro-3h-1,3-benzothiazole-2-thione Chemical compound ClC1=CC=C2SC(S)=NC2=C1 NKYDKCVZNMNZCM-UHFFFAOYSA-N 0.000 description 1
- HOASVNMVYBSLSU-UHFFFAOYSA-N 6-ethoxy-3h-1,3-benzothiazole-2-thione Chemical compound CCOC1=CC=C2N=C(S)SC2=C1 HOASVNMVYBSLSU-UHFFFAOYSA-N 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000007171 acid catalysis Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000010408 film Substances 0.000 description 1
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- 238000009396 hybridization Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
Abstract
The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of a chiral beta-amino derivative. The preparation method of the chiral beta-amino derivative comprises the following steps: providing azetidine quaternary ammonium salt shown in a formula I and nucleophilic reagent shown in a formula II; dissolving the azetidine quaternary ammonium salt and the nucleophilic reagent in a first organic solvent, and carrying out asymmetric ring-opening reaction under the conditions of inorganic base and the catalyst shown in the formula III to obtain the chiral beta-amino derivative shown in the formula IV. The invention adopts chiral catalyst of chiral phosphoric acid, can effectively form chiral phosphate, promotes the generation of ion exchange of a reaction system, and further obtains the chiral beta-amino derivative product with high efficiency and high selectivity. Therefore, the preparation method has the advantages of simple and easily-controlled reaction conditions, high selectivity and high purity of the obtained product.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of a chiral beta-amino derivative.
Background
Chiral beta-amino derivatives are chemical structures that are widely found in active natural products and drug molecules. The existing synthesis method of chiral beta-amino derivatives generally needs multi-step chemical conversion or catalysis by transition metals, the process often needs to prepare a chiral substrate in advance, and the reaction conditions are harsh, and high temperature and strong base are needed, so that the tolerance of functional groups is relatively limited. Therefore, the development of a preparation of the multi-functionalized chiral beta-amino derivative with mild conditions, no metal participation and a divergent mode is very important.
Quaternary ammonium salts occupy an important position in asymmetric catalysis. However, the existing preparation methods of chiral β -amino derivatives mainly use quaternary ammonium salts as catalysts and reagents, and research on using quaternary ammonium salts as reaction substrates or chiral amine sources is relatively limited. Moreover, due to various limitations in terms of reaction activity and stereochemical control, the realization of ring-opening and de-symmetry reactions between asymmetric molecules under mild conditions is more difficult based on catalysis of quaternary ammonium salt and chiral ion pairs, so that the large-scale synthesis of chiral beta-amino derivatives is limited, and the application of the chiral beta-amino derivatives is further influenced.
Disclosure of Invention
The invention aims to overcome the defects in the prior art, provides a preparation method of a multifunctional chiral beta-amino derivative, and aims to solve the technical problems that the existing preparation method of the chiral beta-amino derivative has long steps, is complex to operate, has poor functional group compatibility, needs metal participation, and further limits large-scale synthesis and application of the chiral beta-amino derivative.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a preparation method of chiral beta-amino derivatives, which comprises the following steps:
providing azetidine quaternary ammonium salt shown in a formula I and nucleophilic reagent shown in a formula II;
dissolving the azetidine quaternary ammonium salt and the nucleophilic reagent in a first organic solvent, and performing asymmetric ring-opening reaction under the conditions of inorganic base and a catalyst shown as a formula III to obtain a chiral beta-amino derivative shown as a formula IV;
wherein X is an anion, Nu is a nucleophilic group, Ar1And Ar2Are all aryl groups.
Correspondingly, the invention also provides a preparation method of the amino olefin derivative, which comprises the following steps:
obtaining a compound shown as a formula VI by using the preparation method;
dissolving the compound shown in the formula VI in a second organic solvent, and carrying out oxidation reaction with hydrogen peroxide to obtain an intermediate shown in the formula VII;
dissolving the intermediate shown in the formula VII in a third organic solvent, and sequentially adding hexamethyldisilazane-based amino potassium and aryl aldehyde to react to obtain the amino olefin derivative shown in the formula VIII.
Wherein, Ar in the formula VIII3Is an aryl group.
Accordingly, the present invention also provides a process for the preparation of a compound comprising the steps of:
obtaining a compound shown as a formula VI by using the preparation method;
dissolving the compound shown in the formula VI in a fourth organic solvent, and adding triethylsilylhydride for elimination reaction to obtain a compound shown in the formula IX;
in the preparation method of the chiral beta-amino derivative, polyfunctional group substituted 3-substituted azetidine quaternary ammonium salt shown in formula I and nucleophilic reagent shown in formula II are used as reaction substrates, organic base and chiral phosphoric acid catalyst CPA (1, 10-diaryl substituted spirocyclic diphenol phosphonate ester, the molecular structure is shown in formula III) are used for catalysis, asymmetric intermolecular ring opening reaction occurs, due to the chiral intermolecular azetidine quaternary ammonium salt ring opening reaction and difficulty, the selection of the catalyst and the base plays an important role in success or failure of the whole reaction, the chiral catalyst of the chiral phosphoric acid adopted in the invention can effectively form chiral phosphate, further promotes the generation of ion exchange of a reaction system, and thus the chiral beta-amino derivative product is obtained efficiently and highly selectively. Therefore, the preparation method has the advantages of simple and easily-controlled reaction conditions, high selectivity and high purity of the obtained product.
According to the preparation method of the amino olefin derivative shown in the formula VIII and the compound shown in the formula IX, the chiral beta-amino derivative obtained by the preparation method of the chiral beta-amino derivative is subjected to chemical conversion, so that the preparation of a useful chemical structure can be realized in a diversified manner, and the preparation method has the characteristics of simple and easily-controlled reaction conditions, high selectivity and high purity of the obtained product.
Detailed Description
In order to make the technical problems, technical solutions and advantageous effects to be solved by the present invention more clearly apparent, the present invention is further described in detail below with reference to the following 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.
The embodiment of the invention provides a preparation method of a multifunctional chiral beta-amino derivative, which comprises the following steps:
s01: providing azetidine quaternary ammonium salt shown in a formula I and nucleophilic reagent shown in a formula II;
s02: dissolving the azetidine quaternary ammonium salt and the nucleophilic reagent in a first organic solvent, and performing asymmetric ring-opening reaction under the conditions of inorganic base and a catalyst shown as a formula III to obtain a chiral beta-amino derivative shown as a formula IV;
wherein X is an anion, Nu is a nucleophilic group, Ar1And Ar2Are all aryl groups.
Based on catalysis of quaternary ammonium salt and chiral ion pairs, the ring-opening and de-symmetry reaction between asymmetric molecules is realized under mild conditions, and the following difficulties exist: firstly, the method comprises the following steps: when the azetidine quaternary ammonium salt is used as a reactant, the ring opening and the three-dimensional control of an azetidine skeleton are difficult to realize by a traditional asymmetric catalysis strategy (such as chiral protonic acid catalysis) because a proper activation site is not provided. Secondly, the method comprises the following steps: chiral anion control is critical from a reaction mechanism point of view. Because nitrogen atom of azetidine quaternary ammonium salt adopts sp3Hybridization, in a spatial tetrahedral arrangement, makes the mode of action of the chiral anion and the quaternary ammonium cation difficult to predict and regulate, resulting in a great challenge to control the chemistry and stereoselectivity of the reaction. Thirdly, the method comprises the following steps: how to find out the mutually matched reaction conditions (including the selection of a solvent, an inorganic base, a nucleophilic reagent and the like) is a great difficulty in ensuring that the reaction can be smoothly carried out, effectively inhibiting the background reaction and not influencing the control of enantioselectivity. Fourthly: azetidine quatemary ammonium salts may be presentThe cis-trans isomers also bring great difficulty to the acquisition of high enantioselectivity of the corresponding ring-opening reaction.
Based on the above factors, so far, the asymmetric organic catalytic reaction in which the quaternary ammonium salt participates becomes a difficult problem to overcome, and the ring-opening reaction of the organically catalyzed asymmetric azetidine quaternary ammonium salt is not reported. The inventor of the invention carries out intensive research, and utilizes the catalytic asymmetric intermolecular ring-opening de-symmetry reaction to synthesize the multi-functionalization chiral beta-amino derivative in one step, thereby having important application value. In the preparation method of the chiral beta-amino derivative provided by the embodiment of the invention, multifunctional group substituted 3-substituted azetidine quaternary ammonium salt and nucleophilic reagent are used as reaction substrates, organic base and phosphoric acid catalyst CPA (shown as formula III) with a chiral spiro skeleton are used for catalysis to generate asymmetric intermolecular ring opening reaction, and due to the ring opening reaction and difficulty of chiral intermolecular azetidine quaternary ammonium salt, the selection of the catalyst and the base plays an important role in success or failure of the whole reaction. Therefore, the preparation method has the advantages of simple and easily-controlled reaction conditions, high selectivity and high purity of the obtained product.
Further, in the above step S01, in the catalyst structural formula shown in formula III, Ar1And Ar2Any one selected from phenyl, naphthyl, 9-phenanthryl, 9-anthryl, 1-pyrenyl, 3, 5-bistrifluoromethylphenyl and 2,4, 6-tricyclohexylphenyl. In a preferred embodiment of the present invention, Ar1And Ar2The catalyst is 2,4, 6-tricyclohexylphenyl or 9-anthryl, namely two chiral catalysts, namely 2,4, 6-tricyclohexylphenyl substituted chiral spiro backbone phosphoric acid and 9-anthryl substituted chiral spiro backbone phosphoric acid, and the ee value of a product obtained by catalyzing the two catalysts is the largest.
Further, in step S01, in the structural formula of azetidine quaternary ammonium salt shown in formula I, R is1And R2Is benzene ring or substituted benzene ring, condensed ring or substituted condensed ring, heterocycle,Any one of alkenyl, alkyl, benzyl, cyano, ester group, amide, ether, amino and hydrogen atom. More specifically, the substituted benzene ring, the substituted fused ring, the substituted group includes but is not limited to halogen, methyl, methoxy, trifluoromethoxy, trifluoromethyl, acetal, the heterocycle includes but is not limited to furan, thiophene, and the anion X includes but is not limited to trifluoromethanesulfonic acid anion and tetrafluoroboric acid anion.
Further, in the step S01, the nucleophile represented by the formula II is 2-mercaptoarylthiazole represented by the formula V,
wherein R is5Is one of hydrogen atom, halogen, methyl, methoxyl and ethoxyl.
Further, in the step S02, due to the technical difficulty in the ring-opening reaction process of the chiral intermolecular azetidinium quaternary ammonium salt, the selection of the catalyst and the base is important to the success or failure of the whole reaction. In a preferred embodiment of the invention, 2,4, 6-tricyclohexylphenyl or 9-anthryl substituted chiral spiro backbone phosphoric acid is used as chiral catalyst. While the inorganic base is selected from various kinds, including Na2HPO4、Na3PO4、K2HPO4、K3PO4、Na2CO3、NaHCO3And K2CO3In a preferred embodiment of the invention, the inorganic salt is selected from Na2HPO4Thus, under the conditions of the preferred catalyst and inorganic salt, the chiral sodium phosphate salt can be effectively formed, the ion exchange of the reaction system is effectively promoted, namely the chiral sodium phosphate salt provides the chiral anion to perform the ion exchange with the anion of the azetidine quaternary ammonium salt, so as to form a chiral ion pair intermediate, and then the intermediate is subjected to the attack of a nucleophilic reagent to perform the ring-opening reaction. Preferably, the addition amount of the catalyst CPA is 10% of the molar amount of the azetidine quaternary ammonium salt shown in the formula I, and the addition amount of the inorganic base is 10% of the molar amount of the azetidine quaternary ammonium salt shown in the formula I200% of the molar amount of the azetidine quaternary ammonium salt of (a), if the catalyst CPA is added in an amount lower than the molar amount, the ee value is reduced.
In step S02, the azetidine quaternary ammonium salt shown in formula I, the nucleophile shown in formula II, the inorganic base, and the CPA catalyst are weighed and mixed, and then a first organic solvent is added, where the first organic solvent is an organic solvent that can dissolve the 2-mercaptoarylthiazole and the catalyst at the same time, but does not react with the reactant, and includes but is not limited to one of dichloromethane, 1, 2-dichloroethane, chloroform, toluene, fluorobenzene, and trifluorotoluene. The first organic solvent such as trifluorotoluene is added in an amount such that the concentration of the 3-substituted azetidine quaternary ammonium salt is 0.020 to 0.2mol/L, more preferably 0.025 mol/L. If the amount of the first organic solvent is too high or too low, the concentration of the 3-substituted azetidine quaternary ammonium salt is correspondingly reduced or increased, resulting in a reduction in ee value.
In a preferred embodiment of the invention, under the conditions of the provided reaction raw materials and a specific catalyst, asymmetric intermolecular ring opening reaction is carried out at the temperature of 5-30 ℃ and under stirring conditions to obtain the chiral beta-amino derivative shown as the formula IV, which is shown as the following formula:
specifically, the reaction temperature may be 5 ℃ or room temperature, and in the embodiment of the present invention, the room temperature may be specifically 24 to 28 ℃.
Correspondingly, the embodiment of the invention also provides a preparation method of the amino olefin derivative, which comprises the following steps:
e01: obtaining a compound shown in a formula VI by using the preparation method of the chiral beta-amino derivative;
e02: dissolving the compound shown in the formula VI in a second organic solvent, and carrying out oxidation reaction with hydrogen peroxide to obtain an intermediate shown in the formula VII;
e03: dissolving the intermediate shown in the formula VII in a third organic solvent, and sequentially adding hexamethyldisilazane-based amino potassium and aryl aldehyde to react to obtain the amino olefin derivative shown in the formula VIII.
Wherein, Ar in the formula VIII3Is an aryl group.
Further, in the above step E02, after the chiral β -amino derivative represented by the formula VI is dissolved in the second organic solvent, CF is added3CO2And H, reacting for 15 minutes at room temperature under the condition of stirring, and cooling to 0 ℃. Then, (NH) is added4)6Mo7O24·4H2And (3) reacting the mixed solution of O and hydrogen peroxide (35%) at room temperature under stirring to obtain the intermediate shown in the formula VII. And dissolving the intermediate shown in the formula VII in a third organic solvent, cooling to-78 ℃, adding hexamethyldisilazane (KHMDS), reacting for half an hour at constant temperature, adding aryl aldehyde, reacting for one hour at constant temperature, and reacting under the condition of stirring at room temperature to obtain the amino olefin derivative shown in the formula VIII.
Specifically, the second organic solvent is an organic solvent that can effectively dissolve the reactant and does not chemically react with the reactant, and is preferably MeOH. In the reaction system of the example of the present invention, the CF3CO2H is used as an acidic substance, can protonate amino groups and provides a better reaction state for subsequent reaction; and said (NH)4)6Mo7O24·4H2O can effectively activate hydrogen peroxide, so that thioether can be selectively oxidized. Firstly cooling to 0 ℃ to avoid over violent heat release of the initial reaction, and then stirring at room temperature to obtain the chiral beta-amino derivative shown as the formula VI and H2O2The reaction to give the product of formula VII is shown below:
further, in the step E03, the intermediate shown in the formula VII is dissolved in a third organic solvent, cooled to-78 ℃ to avoid the excessively violent reaction heat and side reaction, and after adding the potassium hexamethyldisilazide (KHMDS), the reaction is carried out for half an hour at constant temperature. Wherein the third organic solvent is an organic solvent which can effectively dissolve the reactant and does not chemically react with the reactant, and is preferably tetrahydrofuran. Then adding aryl aldehyde, reacting for one hour at constant temperature, and reacting under the condition of stirring at room temperature to obtain a product shown in a formula VIII, wherein the reaction formula is as follows:
the embodiment of the invention also provides a preparation method of the compound, which comprises the following steps:
t01: obtaining a compound shown in a formula VI by using the preparation method of the chiral beta-amino derivative;
t02: dissolving the compound shown in the formula VI in a fourth organic solvent, and adding triethylsilylhydride for elimination reaction to obtain a compound shown in the formula IX;
further, in the above step T02, the compound represented by the formula VI is dissolved in a fourth organic solvent, and triethylsilylhydride is added dropwise to the solution to react at 85 ℃ with stirring. The chiral beta-amino derivative and triethylhydrosilane are dissolved in a fourth organic solvent, and in order to ensure the stability and reliability of the reaction, the reaction is carried out at the temperature of 85-90 ℃. Specifically, the fourth organic solvent is an organic solvent which can dissolve the chiral beta-amino derivative and the triethylhydrosilane and does not chemically react with the reactant, and is preferably CF3CO2H. Stirring the mixture to obtain a compound shown as a formula IX, which is shown as the following reaction formula:
according to the preparation methods of the aminoalkene derivative shown in the formula VIII and the compound shown in the formula IX, the chiral beta-amino derivative obtained by the preparation method of the chiral beta-amino derivative is used for chemical conversion, the preparation of a useful chemical structure can be realized in a diversified manner, and the preparation methods also have the characteristics of simple and easily-controlled reaction conditions, high selectivity and high purity of the obtained product.
The invention is described in further detail with reference to a part of the test results, which are described in detail below with reference to specific examples.
Example 1
By the use of R1＝Ph,R2＝H,R3＝Me,R4＝Ph2CH,X＝-3-substituted azetidinium quaternary ammonium salts of OTf and R5Mercaptobenzothiazole as 6-OEt as reaction raw material and Na2HPO4The alkali is reacted by using a chiral phosphoric acid catalyst CPA, and the specific implementation process is as follows:
N-benzhydryl-N-methyl-3-phenylazetidine triflate (92.7mg,0.2mmol), 6-ethoxy-2-mercaptobenzothiazole (84.6mg,0.4mmol), disodium hydrogen phosphate (56.8mg,0.4mmol) and catalyst (19.2mg,0.02mmol) were weighed into a 25mL dry round bottom flask, benzotrifluoride (8mL) was added and stirred at ambient temperature for 96 hours. The reaction equation is as follows:
the reaction solution was directly subjected to silica gel column chromatography to give 101.7mg of a white foam product, which was calculated to have a yield of 97%. And analyzing the obtained foam product by measuring specific optical rotation, and measuring an ee value, nuclear magnetic resonance, infrared and high-resolution mass spectrum by high performance liquid chromatography. The assay of the test is as follows:
specific optical rotation [ alpha ] measured at 1.25 ℃ on D line]D 25:-32.3(c＝1.0,CHCl3)。
2. Determination of ee value by high performance liquid chromatography: chiral column Daicel
An AD-H column; 1% i-PrOH inhexanes; 1.0 mL/min; retention time 8.6min (minor),9.2min (major). The calculated result was 90% ee.
3. Hydrogen spectrum, carbon spectrum of nuclear magnetic resonance analysis:
1H NMR(400MHz,CDCl3)7.76(d,J＝8.0Hz,1H),7.41(d,J＝8.0Hz,2H),7.38-7.19(m,12H),7.14(d,J＝6.8Hz,2H),7.04(dd,J＝8.8,2.8Hz,1H),4.46(s,1H),4.16-4.05(m,3H),3.48-3.35(m,2H),2.87-2.77(m,1H),2.62-2.54(m,1H),2.32(s,3H),1.48(t,J＝7.2Hz,3H)ppm.
13C NMR(100MHz,CDCl3)164.0,156.2,147.8,142.8,142.6,142.0,136.5,128.34(2C),128.27,128.2,128.1,127.9,126.9,126.85,126.80,121.8,115.1,104.8,75.9,64.1,61.0,43.9,40.5,37.8,14.8ppm。
4. infrared spectrum: IR (thin film)2926,1598,1446,1220,938,696cm-1。
5. High resolution mass spectrometry: HRMS (CI +) Calcd for C32H33N2OS2[M++H]:525.2034,Found:525.2039。
From the results, it can be seen that the theoretical mass is 525.2034, while the observed value of the peak found in the actual mass spectrum is 525.2039; the following structure of the product can be determined by combining nuclear magnetic resonance and infrared elemental analysis and standard specific optical rotation:
Example 2
By the use of R1＝4-OCF3C6H4,R2＝H,R3＝Me,R4＝Ph2CH,X＝-3-substituted azetidinium quaternary ammonium salts of OTf and R5Mercaptobenzothiazole as 6-OEt as reaction raw material, Na2HPO4The reaction was carried out with 10% chiral phosphoric acid catalyst as a base according to the same procedure as described in example 1 above for 96 hours to give 113.2 as a white foam productmg, calculated yield 93%. And analyzing the obtained foam product by measuring specific optical rotation, and measuring an ee value, nuclear magnetic resonance, infrared and high-resolution mass spectrum by high performance liquid chromatography. Wherein, the test analysis data is as follows:
specific optical rotation [ alpha ] measured at 1.25 ℃ on D line]D 25:-38.2(c＝1.0,CHCl3)。
2. Determination of ee value by high performance liquid chromatography: chiral column Daicel
An AD-H column; 1% i-PrOH inhexanes; 1.0 mL/min; retention time 7.6min (major),7.9min (minor). The calculated result was 94% ee.
3. Hydrogen, carbon, fluorine spectra of nmr analysis:
1H NMR(400MHz,CDCl3)7.73(d,J＝8.8Hz,1H),7.35(d,J＝7.2Hz,2H),7.32-7.19(m,9H),7.18-7.09(m,4H),7.02(dd,J＝8.8,2.4Hz,1H),4.42(s,1H),4.07(q,J＝6.8Hz,2H),4.01(dd,J＝12.4,4.8Hz,1H),3.49-3.30(m,2H),2.75(dd,J＝12.4,7.6Hz,1H),2.56(dd,J＝12.4,7.2Hz,1H),2.28(s,3H),1.46(t,J＝7.2Hz,3H)ppm.
13C NMR(100MHz,CDCl3)163.5,156.4,148.0,147.7,142.6,142.4,140.7,136.5,129.3,128.4,128.3,128.2,128.1,126.94,126.92,121.9,120.8,120.5(d,JC-F＝255Hz),115.2,104.8,75.9,64.1,60.8,43.5,40.5,37.6,14.8ppm.
19F NMR(376MHz,CDCl3)-57.8ppm。
4. infrared spectrum: IR (thin film)2979,1599,1447,1219,997,938,821,705cm-1。
5. High resolution mass spectrometry: HRMS (CI +) Calcd for C33H32N2O2S2F3[M++H]:609.1857,Found:609.1857。
From the results, it can be seen that the theoretical mass is 609.1857, while the observed value of the peak found in the actual mass spectrum is 609.1857; the following structure of the product can be determined by combining nuclear magnetic resonance and infrared elemental analysis and standard specific optical rotation:
Example 3
By the use of R1＝4-FC6H4,R2＝H,R3＝Me,R4＝Ph2CH,X＝-3-substituted azetidinium quaternary ammonium salts of OTf and R5Mercaptobenzothiazole as 6-OEt as reaction raw material, Na2HPO4The reaction was carried out using 10% chiral phosphoric acid as a base, and the same procedure as described in example 1 above was followed for 96 hours to give 100.8mg of a white foam product in a calculated yield of 93%. And analyzing the obtained foam product by measuring specific optical rotation, and measuring an ee value, nuclear magnetic resonance, infrared and high-resolution mass spectrum by high performance liquid chromatography. Wherein, the test analysis data is as follows:
specific optical rotation [ alpha ] measured at 1.25 ℃ on D line]D 25:-30.3(c＝1.0,CHCl3)。
2. Determination of ee value by high performance liquid chromatography: chiral column Daicel
An AD-H column; 1% i-PrOH inhexanes; 1.0 mL/min; the retention time is 9.9min (minor),10.3min (major). The calculated result was 94% ee.
3. Hydrogen, carbon, fluorine spectra of nmr analysis:
1H NMR(400MHz,CDCl3)7.74(d,J＝8.8Hz,1H),7.37(d,J＝7.2Hz,2H),7.34-7.16(m,9H),7.10-6.95(m,5H),4.43(s,1H),4.12-3.98(m,3H),3.42-3.29(m,2H),2.78-2.72(m,1H),2.58-2.52(m,1H),2.28(s,3H),1.46(t,J＝7.2Hz,3H)ppm.
13C NMR(100MHz,CDCl3)163.7,161.8(d,JC-F＝243Hz),156.3,147.7,142.7,142.5,137.71,137.68,136.5,129.4,129.3,128.3(d,JC-F＝7.1Hz),128.2,128.1,126.9(d,JC-F＝3.3Hz),121.8,115.2(d,JC-F＝44Hz),115.0,104.8,75.9,64.1,61.0,43.2,40.5,37.8,14.8ppm.
19F NMR(376MHz,CDCl3)-115.9ppm。
4. infrared spectrum: IR (thin film)2977,1599,1445,1220,996,821,704cm-1。
5. High resolution mass spectrometry: HRMS (CI +) Calcd for C32H32N2OS2F[M++H]:543.1940,Found:543.1929。
From the results, it can be seen that the theoretical mass is 543.1940, while the observed value of the peak found in the actual mass spectrum is 543.1929; the following structure of the product can be determined by combining nuclear magnetic resonance and infrared elemental analysis and standard specific optical rotation:
Example 4
By the use of R1＝3-OMeC6H4,R2＝H,R3＝Me,R4＝Ph2CH,X＝-3-substituted azetidinium quaternary ammonium salts of OTf and R5Mercaptobenzothiazole as 6-OEt as reaction raw material, Na2HPO4The reaction was carried out using 10% chiral phosphoric acid as a base, and according to the same procedure as described in example 1 above, the reaction was carried out for 96 hours to give 107.5mg of a white foam product in a calculated yield of 97%. And analyzing the obtained foam product by measuring specific optical rotation, and measuring an ee value, nuclear magnetic resonance, infrared and high-resolution mass spectrum by high performance liquid chromatography. Wherein, the test analysis data is as follows:
specific optical rotation [ alpha ] measured at 1.25 ℃ on D line]D 25:-36.1(c＝1.0,CHCl3)。
2. Determination of ee value by high performance liquid chromatography: chiral column Daicel
An AD-H column; 2% i-PrOH inhexanes; 1.0 mL/min; retention time 12.6min (minor)14.9min (major). The calculated result was 96% ee.
3. Hydrogen spectrum, carbon spectrum of nuclear magnetic resonance analysis:
1H NMR(400MHz,CDCl3)7.76(d,J＝8.8Hz,1H),7.44-7.30(m,4H),7.30-7.18(m,8H),7.03(d,J＝8.8Hz,1H),6.81(d,J＝7.6,1H),6.73(d,J＝7.6,1H),6.67(s,1H),4.46(s,1H),4.15-4.04(m,3H),3.79(s,3H),3.46-3.38(m,2H),2.85-2.76(m,1H),2.62-2.54(m,1H),2.31(s,3H),1.47(t,J＝7.2Hz,3H)ppm.
13C NMR(100MHz,CDCl3)164.0,159.5,156.2,147.7,143.7,142.7,142.6,136.5,129.3,128.33,128.26,128.2,128.1,126.9,126.8,121.8,120.3,115.1,113.8,112.0,104.8,75.9,64.0,61.0,55.1,44.0,40.5,37.7,14.8ppm。
4. infrared spectrum: IR (thin film)2906,1597,1444,1219,991,819,693cm-1。
5. High resolution mass spectrometry: HRMS (CI +) Calcd for C33H33N2O2S2[M+-H]:553.1978,Found:553.2001。
From the results, it can be seen that the theoretical mass is 553.1978, while the observed value of the peak found in the actual mass spectrum is 553.2001; the following structure of the product can be determined by combining nuclear magnetic resonance and infrared elemental analysis and standard specific optical rotation:
Example 5
By the use of R1＝3-CF3C6H4,R2＝H,R3＝Me,R4＝Ph2CH,X＝-3-substituted azetidinium quaternary ammonium salts of OTf and R5Mercaptobenzothiazole as 6-OEt as reaction raw material, Na2HPO4The reaction was carried out using 10% chiral phosphoric acid as a base, and according to the same procedure as described in example 1 above, the reaction was carried out for 96 hours to give 111.3mg of a white foam product in a calculated yield of 94%. Analyzing the obtained foam product, and means for analyzingThe specific optical rotation is measured, and the ee value, nuclear magnetic resonance, infrared and high-resolution mass spectra are measured by high performance liquid chromatography. Wherein, the test analysis data is as follows:
specific optical rotation [ alpha ] measured at 1.25 ℃ on D line]D 25:-36.1(c＝1.0,CHCl3)。
2. Determination of ee value by high performance liquid chromatography: chiral column Daicel
An AD-H column; 1% i-PrOH inhexanes; 1.0 mL/min; retention time 6.6min (minor),7.0min (major). The calculated result was 90% ee.
3. Hydrogen, carbon, fluorine spectra of nmr analysis:
1H NMR(400MHz,CDCl3)7.73(d,J＝8.8Hz,1H),7.52(d,J＝7.6Hz,1H),7.45-7.38(m,2H),7.33(d,J＝7.6Hz,3H),7.29-7.14(m,9H),7.01(dd,J＝8.8,2.4Hz,1H),4.41(s,1H),4.07(q,J＝6.8Hz,2H),3.94(dd,J＝12.4,4.8Hz,1H),3.49-3.36(m,2H),2.78-2.69(m,1H),2.68-2.59(m,1H),2.26(s,3H),1.45(t,J＝7.2Hz,3H)ppm.
13C NMR(100MHz,CDCl3)163.2,156.4,147.7,143.1,142.7,142.4,136.5,131.5,130.5(q,JC-F＝31.8Hz),128.7,128.39,128.35,128.1,128.0,126.9(d,JC-F＝2.4Hz),124.8(d,JC-F＝3.8Hz),124.2(d,JC-F＝271Hz),123.7(d,JC-F＝3.8Hz),121.9(2C),115.2,104.8,76.0,64.1,60.6,44.0,40.5,37.3,14.8ppm。
19F NMR(376MHz,CDCl3)-62.3ppm.
4. infrared spectrum: IR (thin film)2980,1599,1445,1326,1119,938,821,697cm-1。
5. High resolution mass spectrometry: calcd for C33H32F3N2OS2[M++H]:593.1908,Found:593.1911。
From the results, it can be seen that the theoretical mass is 593.1908, while the observed value of the peak found in the actual mass spectrum is 593.1911; the following structure of the product can be determined by combining nuclear magnetic resonance and infrared elemental analysis and standard specific optical rotation:
Example 6
By the use of R1＝3,4-(OCH2O)C6H3,R2＝H,R3＝Me,R4＝Ph2CH,X＝-3-substituted azetidinium quaternary ammonium salts of OTf and R5Mercaptobenzothiazole as 6-OEt as reaction raw material, Na2HPO4The reaction was carried out using 10% chiral phosphoric acid as a base, and the same procedure as described in example 1 above was followed for 96 hours to give 110.2mg of a white foam product in 97% calculated yield. And analyzing the obtained foam product by measuring specific optical rotation, and measuring an ee value, nuclear magnetic resonance, infrared and high-resolution mass spectrum by high performance liquid chromatography. Wherein, the test analysis data is as follows:
specific optical rotation [ alpha ] measured at 1.25 ℃ on D line]D 25:-36.1(c＝1.0,CHCl3)。
2. Determination of ee value by high performance liquid chromatography: chiral column Daicel
An AD-H column; 5% i-PrOH inhexanes; 1.0 mL/min; the retention time is 11.0min (minor),13.1min (major). The calculated result was 92% ee.
3. Hydrogen spectrum, carbon spectrum of nuclear magnetic resonance analysis:
1H NMR(400MHz,CDCl3)7.74(d,J＝8.8Hz,1H),7.43-7.37(m,4H),7.37-7.17(m,7H),7.02(d,J＝8.8Hz,1H),6.75(d,J＝7.6Hz,1H),6.62-6.56(m,2H),5.93(d,J＝7.2Hz,2H),4.44(s,1H),4.13-3.99(m,3H),3.35-3.26(m,2H),2.79-2.71(m,1H),2.56-2.48(m,1H),2.28(s,3H),1.47(t,J＝7.2Hz,3H)ppm.
13C NMR(100MHz,CDCl3)163.9,156.2,147.7,147.5,146.3,142.7,142.6,136.5,135.8,128.4,128.3,128.2,128.1,126.9,126.8,121.8,121.2,115.1,108.1,108.0,104.8,100.9,75.9,64.0,61.0,43.7,40.5,38.1,14.8ppm。
4. infrared spectrum: IR (thin film)2926,1598,1444,1221,1036,935,806,704cm-1。
5. High resolution mass spectrometry: HRMS (CI +) Calcd for C33H31N2O3S2[M+-H]:567.1771,Found:567.1786。
From the results, it can be seen that the theoretical mass is 567.1771, while the observed value of the peak found in the actual mass spectrum is 567.1786; the following structure of the product can be determined by combining nuclear magnetic resonance and infrared elemental analysis and standard specific optical rotation:
Example 7
By the use of R1＝2-Nap,R2＝H,R3＝Me,R4＝Ph2CH,X＝-3-substituted azetidinium quaternary ammonium salts of OTf and R5Mercaptobenzothiazole as 6-OEt as reaction raw material, Na2HPO4The reaction was carried out using 10% chiral phosphoric acid catalyst as a base, and according to the same procedure as described in example 1 above, the reaction was carried out for 96 hours to give 105.7mg of a white foam product in a calculated yield of 92%. And analyzing the obtained foam product by measuring specific optical rotation, and measuring an ee value, nuclear magnetic resonance, infrared and high-resolution mass spectrum by high performance liquid chromatography. Wherein, the test analysis data is as follows:
specific optical rotation [ alpha ] measured at 1.25 ℃ on D line]D 25:-8.8(c＝1.0,CHCl3)。
2. Determination of ee value by high performance liquid chromatography: chiral column Daicel
An AD-H column; 2% i-PrOH inhexanes; 1.0 mL/min; retention time 12.2min (minor),13.4min (major). The calculated result was 92% ee.
3. Hydrogen spectrum, carbon spectrum of nuclear magnetic resonance analysis:
1H NMR(400MHz,CDCl3)7.86-7.72(m,4H),7.58(s,1H),7.52-7.48(m,2H),7.39-7.18(m,12H),7.02(d,J＝8.8Hz,1H),4.46(s,1H),4.18-4.03(m,3H),3.62-3.48(m,2H),2.92-2.82(m,1H),2.74-2.65(m,1H),2.32(s,3H),1.46(t,J＝6.8Hz,3H)ppm.
13C NMR(100MHz,CDCl3)163.9,156.3,147.8,142.73,142.6,139.5,136.5,133.4,132.6,128.34,128.27,128.2,128.1,128.0,127.7,127.6,126.85,126.81,126.7,126.1,125.9,125.5,121.8,115.1,104.8,76.0,64.1,61.0,44.1,40.6,37.8,14.8ppm。
4. infrared spectrum: IR (thin film)2926,1597,1449,1221,994,908,704cm-1。
5. High resolution mass spectrometry: HRMS (CI +) Calcd for C36H33N2OS2[M+-H]:573.2029,Found:573.2016。
From the results, it can be seen that the theoretical mass is 573.2029, while the observed value of the peak found in the actual mass spectrum is 573.2029; the following structure of the product can be determined by combining nuclear magnetic resonance and infrared elemental analysis and standard specific optical rotation:
Example 8
By the use of R1＝2-thienyl,R2＝H,R3＝Me,R4＝Ph2CH,X＝-3-substituted azetidinium quaternary ammonium salts of OTf and R5Mercaptobenzothiazole as 6-OEt as reaction raw material, Na2HPO4The reaction was carried out using 10% chiral phosphoric acid as a base, and the same procedure as described in example 1 above was followed for 96 hours to give 100.7mg of a white foam product in 95% calculated yield. And analyzing the obtained foam product by measuring specific optical rotation, and measuring an ee value, nuclear magnetic resonance, infrared and high-resolution mass spectrum by high performance liquid chromatography. Wherein, the test analysis data is as follows:
at 1.25 deg.CSpecific optical rotation [ alpha ] measured by D-line]D 25:-29.7(c＝1.0,CHCl3)。
2. Determination of ee value by high performance liquid chromatography: chiral column Daicel
An OD-H column; 5% i-PrOH inhexanes; 1.0 mL/min; retention time 7.0min (major),11.3min (minor). The calculated result was 94% ee.
3. Hydrogen spectrum, carbon spectrum of nuclear magnetic resonance analysis:
1H NMR(400MHz,CDCl3)7.75(d,J＝8.8Hz,1H),7.46-7.38(m,4H),7.34-7.17(m,8H),7.06-6.97(m,1H),6.97-6.94(m,1H),6.86-6.82(m,1H),4.52(s,1H),4.21-4.04(m,3H),3.81-3.71(m,1H),3.42-3.34(m,1H),2.88-2.78(m,1H),2.67-2.58(m,1H),2.32(s,3H),1.47(t,J＝7.2Hz,3H)ppm.
13C NMR(100MHz,CDCl3)163.7,156.3,147.7,145.4,142.5,142.4,136.5,128.4,128.3,128.24,128.22,126.9,126.8,126.6,124.6,123.6,121.8,115.2,104.8,75.6,64.1,61.6,40.4,39.5,38.7,14.8ppm。
4. infrared spectrum: IR (thin film)2926,1598,1446,1221,1114,996,938,820cm-1。
5. High resolution mass spectrometry: HRMS (CI +) Calcd for C30H31N2OS3[M++H]:531.1599,Found:531.1600。
From the results, it can be seen that the theoretical mass is 531.1599, while the observed value of the peak found in the actual mass spectrum is 531.1600; the following structure of the product can be determined by combining nuclear magnetic resonance and infrared elemental analysis and standard specific optical rotation:
Example 9
By the use of R1＝vinyl,R2＝H,R3＝Me,R4＝Ph2CH,X＝-3-substituted azetidinium quaternary ammonium salts of OTf and R5Mercaptobenzothiazole as 6-OEt as reaction raw material, Na2HPO4The reaction was carried out using 10% chiral phosphoric acid as a base, and the same procedure as described in example 1 above was followed for 96 hours to give 80.6mg of a white foam product in 85% calculated yield. And analyzing the obtained foam product by measuring specific optical rotation, and measuring an ee value, nuclear magnetic resonance, infrared and high-resolution mass spectrum by high performance liquid chromatography. Wherein, the test analysis data is as follows:
specific optical rotation [ alpha ] measured at 1.25 ℃ on D line]D 25:+1.8(c＝1.0,CHCl3)。
2. Determination of ee value by high performance liquid chromatography: chiral column Daicel
An OD-H column; 1% i-PrOH inhexanes; 1.0 mL/min; the retention time is 8.1min (major) and 11.0min (minor). The calculated result was 82% ee.
3. Hydrogen spectrum, carbon spectrum of nuclear magnetic resonance analysis:
1H NMR(400MHz,CDCl3)7.73(d,J＝8.8Hz,1H),7.48-7.40(m,4H),7.32-7.16(m,7H),7.01(dd,J＝8.8,2.4Hz,1H),5.68-5.58(m,1H),5.17-5.08(m,2H),4.43(s,1H),4.07(q,J＝6.8Hz,2H),3.82(dd,J＝12.8,4.8Hz,1H),3.15(dd,J＝12.8,8.8Hz,1H),2.92-2.80(m,1H),2.58-2.49(m,1H),2.36-2.28(m,1H),2.23(s,3H),1.45(t,J＝7.2Hz,3H)ppm.
13C NMR(100MHz,CDCl3)164.3,156.3,147.8,142.7,138.9,136.5(2C),128.4,128.3,128.2(2C),126.9(2C),121.8,116.8,115.1,104.8,75.9,64.1,59.4,42.0,40.3,36.5,14.8ppm。
4. infrared spectrum: IR (thin film)2922,2848,1599,1446,1221,994,696cm-1。
5. High resolution mass spectrometry: HRMS (CI +) Calcd for C28H31N2OS2[M++H]:475.1878,Found:475.1898。
From the results, it can be seen that the theoretical mass is 475.1878, while the observed value of the peak found in the actual mass spectrum is 475.1898; the following structure of the product can be determined by combining nuclear magnetic resonance and infrared elemental analysis and standard specific optical rotation:
Example 10
By the use of R1＝CN,R2＝H,R3＝Me,R4＝Ph2CH,X＝-3-substituted azetidinium quaternary ammonium salts of OTf and R5Mercaptobenzothiazole as 6-OEt as reaction raw material, Na2HPO4The reaction was carried out using 10% chiral phosphoric acid as a base, and the same procedure as described in example 1 above was followed for 3 hours to give 91.8mg of a white foam product in 97% calculated yield. And analyzing the obtained foam product by measuring specific optical rotation, and measuring an ee value, nuclear magnetic resonance, infrared and high-resolution mass spectrum by high performance liquid chromatography. Wherein, the test analysis data is as follows:
specific optical rotation [ alpha ] measured at 1.25 ℃ on D line]D 25:-24.1(c＝1.0,CHCl3)。
2. Determination of ee value by high performance liquid chromatography: chiral column Daicel
An AD-H column; 5% i-PrOH inhexanes; 1.0 mL/min; retention time 13.0min (minor),15.4min (major). The calculated result was 96% ee.
3. Hydrogen spectrum, carbon spectrum of nuclear magnetic resonance analysis:
1H NMR(400MHz,CDCl3)7.75-7.68(m,1H),7.52-7.43(m,4H),7.37-7.30(m,4H),7.30-7.20(m,3H),7.03(d,J＝8.8Hz,1H),4.54(s,1H),4.07(q,J＝6.8Hz,2H),3.86(dd,J＝13.6,5.6Hz,1H),3.62-3.55(m,1H),3.26(dd,J＝13.6,8.8Hz,1H),2.85-2.73(m,2H),2.35(s,3H),1.47(t,J＝7.2Hz,3H)ppm.
13C NMR(100MHz,CDCl3)161.3,156.5,147.2,141.8,141.7,136.6,128.5(3C),128.0,127.9,127.2,121.9,120.3,115.3,104.7,75.3,64.0,55.9,40.4,32.7,31.6,14.7ppm。
4. infrared spectrum: IR (thin film)2928,2241,1734,1598,1446,1222,1000,938,705cm-1。
5. High resolution mass spectrometry: HRMS (CI +) Calcd for C27H28N3OS2[M++H]:474.1674,Found:474.1662。
From the results, it can be seen that the theoretical mass is 474.1674, while the observed value of the peak found in the actual mass spectrum is 474.1662; the following structure of the product can be determined by combining nuclear magnetic resonance and infrared elemental analysis and standard specific optical rotation:
Example 11
By the use of R1＝CO2Me,R2＝H,R3＝Me,R4＝Ph2CH,X＝-3-substituted azetidinium quaternary ammonium salts of OTf and R5Mercaptobenzothiazole as 6-OEt as reaction raw material, Na2HPO4The reaction was carried out using 10% chiral phosphoric acid catalyst as a base, and according to the same procedure as described in example 1 above, the reaction was carried out for 96 hours to give 93.1mg of a white foam product in a calculated yield of 92%. And analyzing the obtained foam product by measuring specific optical rotation, and measuring an ee value, nuclear magnetic resonance, infrared and high-resolution mass spectrum by high performance liquid chromatography. Wherein, the test analysis data is as follows:
specific optical rotation [ alpha ] measured at 1.25 ℃ on D line]D 25:-23.8(c＝1.0,CHCl3)。
2. Determination of ee value by high performance liquid chromatography: chiral column Daicel
An AD-H column; 5% i-PrOH inhexanes; 1.0 mL/min; retention time 9.7min (minor),10.4min (major). The calculated result was 87% ee.
3. Hydrogen spectrum, carbon spectrum of nuclear magnetic resonance analysis:
1H NMR(400MHz,CDCl3)7.71(d,J＝8.8Hz,1H),7.44-7.37(m,4H),7.35-7.24(m,4H),7.24-7.16(m,3H),7.01(dd,J＝8.8,2.4Hz,1H),4.51(s,1H),4.07(q,J＝6.8Hz,2H),3.90-3.80(m,1H),3.72(s,3H),3.40-3.31(m,2H),2.78-2.62(m,2H),2.28(s,3H),1.45(t,J＝7.2Hz,3H)ppm.
13C NMR(100MHz,CDCl3)173.8,162.9,156.3,147.6,142.1,142.1,142.0,136.6,128.4,128.3,128.2,128.1,127.0,121.9,115.2,104.8,75.2,64.0,57.0,51.8,44.8,40.0,33.0,14.8ppm。
4. infrared spectrum: IR (thin film)2977,1734,1598,1446,1220,938,820,703cm-1。
5. High resolution mass spectrometry: HRMS (CI +) Calcd for C28H31N2O3S2[M++H]:507.1776,Found:507.1772。
From the results, it can be seen that the theoretical mass is 507.1776, while the observed value of the peak found in the actual mass spectrum is 507.1772; the following structure of the product can be determined by combining nuclear magnetic resonance and infrared elemental analysis and standard specific optical rotation:
Example 12
By the use of R1＝C(O)NMe(OMe),R2＝H,R3＝Me,R4＝Ph2CH,X＝-3-substituted azetidinium quaternary ammonium salts of OTf and R5Mercaptobenzothiazole as 6-OEt as reaction raw material, Na2HPO4The reaction was carried out using 10% chiral phosphoric acid as a base, and the same procedure as described in example 1 above was followed for 96 hours to give 93.1mg of a white foam product in 87% calculated yield. And analyzing the obtained foam product by measuring specific optical rotation, and measuring an ee value, nuclear magnetic resonance, infrared and high-resolution mass spectrum by high performance liquid chromatography. Wherein, the test analysis data is as follows:
specific optical rotation [ alpha ] measured at 1.25 ℃ on D line]D 25:-46.1(c＝1.0,CHCl3)。
2. Determination of ee value by high performance liquid chromatography: chiral column Daicel
An AD-H column; 10% i-PrOH inhexanes; 1.0 mL/min; the retention time is 11.2min (major) and 12.7min (minor). The calculated result was 76% ee.
3. Hydrogen spectrum, carbon spectrum of nuclear magnetic resonance analysis:
1H NMR(400MHz,CDCl3)7.69(d,J＝8.8Hz,1H),7.48-7.38(m,4H),7.33-7.27(m,4H),7.27-7.15(m,3H),7.00(dd,J＝8.8,2.4Hz,1H),4.56(s,1H),4.06(q,J＝6.8Hz,2H),4.01-3.94(m,1H),3.92-3.82(m,1H),3.54(m,3H),3.40-3.30(m,1H),3.21(s,3H),2.74-2.61(m,2H),2.32(s,3H),1.44(t,J＝7.2Hz,3H)ppm.
13C NMR(100MHz,CDCl3)173.9,163.5,156.3,147.7,142.2,142.1,136.5,128.3,128.19(2C),128.15,128.1,126.9,126.8,121.7,115.1,104.8,75.1,64.0,61.5,57.1,40.4,40.2,33.4,32.1,14.7ppm。
4. infrared spectrum: IR (thin film)2929,1654,1598,1445,1220,994,937,819,704cm-1。
5. High resolution mass spectrometry: HRMS (CI +) Calcd for C29H34N3O3S2[M++H]:536.2042,Found:536.2021。
From the results, it can be seen that the theoretical mass is 536.2042, while the observed value of the peak found in the actual mass spectrum is 536.2021; the following structure of the product can be determined by combining nuclear magnetic resonance and infrared elemental analysis and standard specific optical rotation:
Example 13
By the use of R1＝Bn,R2＝H,R3＝Me,R4＝Ph2CH,X＝-3-substituted azetidinium quaternary ammonium salts of OTf and R5Is 6-OEtMercaptobenzothiazole of (1) as a reaction raw material, Na2HPO4The reaction was carried out using 10% chiral phosphoric acid as a base, and according to the same procedure as described in example 1 above, the reaction was carried out for 96 hours to give 102.3mg of a white foam product in a calculated yield of 95%. And analyzing the obtained foam product by measuring specific optical rotation, and measuring an ee value, nuclear magnetic resonance, infrared and high-resolution mass spectrum by high performance liquid chromatography. Wherein, the test analysis data is as follows:
specific optical rotation [ alpha ] measured at 1.25 ℃ on D line]D 25:-24.1(c＝1.0,CHCl3)。
2. Determination of ee value by high performance liquid chromatography: chiral column Daicel
An AD-H column; 1% i-PrOH inhexanes; 1.0 mL/min; retention time 7.5min (major),8.4min (minor). The calculated result was 86% ee.
3. Hydrogen spectrum, carbon spectrum of nuclear magnetic resonance analysis:
1H NMR(400MHz,CDCl3)7.70(d,J＝8.8Hz,1H),7.43(d,J＝7.2Hz,2H),7.37(d,J＝7.2Hz,2H),7.32-7.14(m,12H),7.01(dd,J＝8.8,2.4Hz,1H),4.42(s,1H),4.08(q,J＝6.8Hz,2H),3.58(dd,J＝12.8,4.8Hz,1H),3.31(dd,J＝12.8,4.8Hz,1H),2.82-2.68(m,2H),2.52-2.38(m,2H),2.38-2.28(m,1H),2.17(s,3H),1.46(t,J＝6.8Hz,3H)ppm.
13C NMR(100MHz,CDCl3)164.4,156.2,147.8,142.7,142.4,139.8,136.5,129.2,128.32,128.28,128.27,128.26,128.2,126.84,126.79,126.0,121.9,115.1,104.8,75.5,64.1,58.8,40.3,39.0,38.2,36.6,14.8ppm。
4. infrared spectrum: IR (thin film)2928,1598,1445,1220,994,938,820,696cm-1。
5. High resolution mass spectrometry: HRMS (CI +) Calcd for C33H35N2OS2[M++H]:539.2191,Found:539.2209。
From the results, it can be seen that the theoretical mass is 539.2191, while the observed value of the peak found in the actual mass spectrum is 539.2191; the following structure of the product can be determined by combining nuclear magnetic resonance and infrared elemental analysis and standard specific optical rotation:
Example 14
By the use of R1Is N- (5-methoxy) indolyl, R2＝H,R3＝Me,R4＝Ph2CH,X＝-3-substituted azetidinium quaternary ammonium salts of OTf and R5Mercaptobenzothiazole as 6-OEt as reaction raw material, Na2HPO4The reaction was carried out using 10% chiral phosphoric acid catalyst as a base, and according to the same procedure as described in example 1 above, the reaction was carried out for 96 hours to give 113.1mg of a white foam product, which was calculated in 91% yield. And analyzing the obtained foam product by measuring specific optical rotation, and measuring an ee value, nuclear magnetic resonance, infrared and high-resolution mass spectrum by high performance liquid chromatography. Wherein, the test analysis data is as follows:
specific optical rotation [ alpha ] measured at 1.25 ℃ on D line]D 25:-12.1(c＝1.0,CHCl3)。
2. Determination of ee value by high performance liquid chromatography: chiral column Daicel
An AD-H column; 10% i-PrOH inhexanes; 1.0 mL/min; retention time 17.1min (major),19.1min (minor). The calculated result was 88% ee.
3. Hydrogen spectrum, carbon spectrum of nuclear magnetic resonance analysis:
1H NMR(400MHz,CDCl3)8.39(s,1H),7.83(d,J＝8.8Hz,1H),7.74(d,J＝8.8Hz,1H),7.32-7.14(m,12H),7.07-6.98(m,2H),6.65-6.60(m,1H),5.22-5.10(m,1H),4.45(s,1H),4.17-4.03(m,3H),3.94(s,3H),3.52(dd,J＝14.0,8.8Hz,1H),3.11-2.98(m,1H),2.96-2.82(m,1H),2.30(s,3H),1.46(t,J＝7.2Hz,3H)ppm.
13C NMR(100MHz,CDCl3)168.1,162.1,156.5,147.4,142.3,142.1,139.1,136.6,128.5,128.0,127.9(2C),127.1,126.1,123.9,122.8,121.8(2C),121.5,115.3(2C),109.4,104.8,103.8,75.8,64.1,58.5,54.5,51.8,41.0,36.7,14.8ppm。
4. infrared spectrum: IR (thin film)2976,1706,1599,1446,1258,1194,997,819,705cm-1。
5. High resolution mass spectrometry: HRMS (CI +) Calcd for C36H34N3O3S2[M+-H]:620.2036,Found:620.2036。
From the results, it can be seen that the theoretical mass is 620.2036, while the observed value of the peak found in the actual mass spectrum is 620.2036; the following structure of the product can be determined by combining nuclear magnetic resonance and infrared elemental analysis and standard specific optical rotation:
Example 15
By the use of R1Is N- (6-bromo) indolyl, R2＝H,R3＝Me,R4＝Ph2CH,X＝-3-substituted azetidinium quaternary ammonium salts of OTf and R5Mercaptobenzothiazole as 6-OEt as reaction raw material, Na2HPO4The reaction was carried out using 10% chiral phosphoric acid as a base, and the same procedure as described in example 1 above was followed for 96 hours to give 119.2mg of a white foam product in a calculated yield of 93%. And analyzing the obtained foam product by measuring specific optical rotation, and measuring an ee value, nuclear magnetic resonance, infrared and high-resolution mass spectrum by high performance liquid chromatography. Wherein, the test analysis data is as follows:
specific optical rotation [ alpha ] measured at 1.25 ℃ on D line]D 25:-66.9(c＝1.0,CHCl3)。
2. Determination of ee value by high performance liquid chromatography: chiral column Daicel
An AD-H column; 2% i-PrOH inhexanes; 1.0 mL/min; the retention time is 10.6min (minor),13.9min (major). Calculating knotThe fruit was 90% ee.
3. Hydrogen spectrum, carbon spectrum of nuclear magnetic resonance analysis:
1H NMR(400MHz,CDCl3)7.83(d,J＝8.8Hz,1H),7.48(d,J＝8.4Hz,1H),7.38-7.31(m,3H),7.31-7.16(m,10H),7.06(dd,J＝9.2,2.4Hz,1H),6.96(d,J＝3.2Hz,1H),6.51(d,J＝3.2Hz,1H),5.07-4.98(m,1H),4.45(s,1H),4.13-4.00(m,3H),3.56(dd,J＝13.6,8.8Hz,1H),3.09-3.01(m,1H),2.95-2.86(m,1H),2.30(s,3H),1.47(t,J＝7.2Hz,3H)ppm.
13C NMR(100MHz,CDCl3)162.1,156.5,147.5,142.4,142.1,137.3,136.6,128.5,128.4,128.1(2C),127.9,127.3,127.1,125.5,122.8,122.0,115.3(2C),115.2,112.9,104.8,102.4,75.9,64.1,58.3,54.5,41.2,36.4,14.8ppm。
4. infrared spectrum: IR (thin film)2776,1598,1446,1220,993,799,696cm-1。
5. High resolution mass spectrometry: HRMS (CI +) Calcd for C34H31BrN3OS2[M+-H]:640.1086,Found:640.1081。
From the results, it can be seen that the theoretical mass is 640.1086, while the observed value of the peak found in the actual mass spectrum is 640.1081; the following structure of the product can be determined by combining nuclear magnetic resonance and infrared elemental analysis and standard specific optical rotation:
Example 16
By the use of R1(ii) N-benzotriazolyl, R2＝H,R3＝Me,R4＝Ph2CH,X＝-3-substituted azetidinium quaternary ammonium salts of OTf and R5Mercaptobenzothiazole as 6-OEt as reaction raw material, Na2HPO4The reaction was carried out using 10% chiral phosphoric acid catalyst as a base, and the same procedure as described in example 1 above was followed for 96 hours to give 100.6mg of a white foam product in 89% calculated yield. The resulting foam product is analyzed by determining the specific rotationAnd (3) determining ee value, nuclear magnetic resonance, infrared and high-resolution mass spectrum by high performance liquid chromatography analysis. Wherein, the test analysis data is as follows:
specific optical rotation [ alpha ] measured at 1.25 ℃ on D line]D 25:-20.1(c＝1.0,CHCl3)。
2. Determination of ee value by high performance liquid chromatography: chiral column Daicel
An AD-H column; 5% i-PrOH inhexanes; 1.0 mL/min; the retention time is 8.9min (minor),11.3min (major). The calculated result was 88% ee.
3. Hydrogen spectrum, carbon spectrum of nuclear magnetic resonance analysis:
1H NMR(400MHz,CDCl3)7.90-7.84(m,2H),7.69(d,J＝8.8Hz,1H),7.42-7.36(m,2H),7.29(d,J＝7.2Hz,2H),7.25-7.14(m,9H),7.00(dd,J＝9.2,2.4Hz,1H),5.72-5.65(m,1H),4.55(s,1H),4.37(dd,J＝14.4,4.0Hz,1H),4.06(q,J＝6.8Hz,2H),3.58(dd,J＝14.4,10.0Hz,1H),3.21-3.10(m,2H),2.36(s,3H),1.45(t,J＝7.2Hz,3H)ppm.
13C NMR(100MHz,CDCl3)162.0,156.4,147.5,144.1,141.9,141.7,136.6,128.33,128.26,128.0(2C),127.0,126.2,121.9,118.1(2C),115.2,104.7,75.0,65.3,64.0,59.6,40.4,36.0,14.8ppm。
4. infrared spectrum: IR (thin film)2936,1626,1450,1219,996,908,816,704cm-1。
5. High resolution mass spectrometry: HRMS (CI +) Calcd for C32H32N5OS2[M++H]:566.2048,Found:566.2054。
From the results, it can be seen that the theoretical mass is 566.2048, while the observed value of the peak found in the actual mass spectrum is 566.2054; the following structure of the product can be determined by combining nuclear magnetic resonance and infrared elemental analysis and standard specific optical rotation:
Example 17
By the use of R1Is N-carbazolyl, R2＝H,R3＝Me,R4＝Ph2CH,X＝-3-substituted azetidinium quaternary ammonium salts of OTf and R5Mercaptobenzothiazole as 5-Cl as reaction raw material, Na2HPO4As a base, the reaction was carried out with 10% chiral phosphoric acid catalyst cpa for 96 hours to give 119.2mg of a white foam product in a calculated yield of 93%. The specific process is as follows:
N-benzhydryl-N-methyl-3- (N-carbazolyl) azetidine trifluoromethanesulfonate (110.5mg,0.2mmol), 5-chloro-2-mercaptobenzothiazole (80.7mg,0.4mmol), disodium hydrogen phosphate (56.8mg,0.4mmol) and a catalyst (13.3mg,0.02mmol) were weighed into a 25mL dry round-bottomed flask, and trifluorotoluene (8mL) was added thereto, and the mixture was stirred at room temperature for 96 hours. The reaction equation is as follows:
the reaction solution was directly used for silica gel column chromatography to obtain 108.6mg of a white foam product, the calculated yield was 90%. After completion of the preparation, the obtained foam product was analyzed by measuring specific optical rotation, measuring ee value by hplc analysis, nmr, ir and high resolution mass spectrometry in order to verify that the purified compound was indeed the target product to be prepared in this example. The assay of the test is as follows:
specific optical rotation [ alpha ] measured at 1.25 ℃ on D line]D 25:-75.2(c＝1.0,CHCl3)。
2. Determination of ee value by high performance liquid chromatography: chiral column Daicel
An AD-H column; 2% i-PrOH inhexanes; 1.0 mL/min; retention time 7.2min (major),7.8min (minor). The calculated result was 86% ee.
3. Hydrogen spectrum, carbon spectrum of nuclear magnetic resonance analysis:
1H NMR(400MHz,CDCl3)8.12-8.04(m,2H),7.82-7.76(m,1H),7.62(d,J＝8.4Hz,1H),7.37-7.13(m,16H),6.91(s,1H),5.56-5.44(m,1H),4.48(s,1H),4.44(dd,J＝14.0,4.8Hz,1H),3.89(dd,J＝14.0,10.0Hz,1H),3.44(dd,J＝13.2,8.0Hz,1H),3.03(dd,J＝12.6,8.0Hz,1H),2.42(s,3H)ppm.
13C NMR(100MHz,CDCl3)168.4,153.8,142.7,142.2,141.7,138.1,133.6,132.1,128.6,128.4,128.1,127.9,127.1,127.0,125.7,125.2,124.6,124.2,122.6,121.6,121.3(2C),120.5,120.0,119.0,110.8,108.7,75.8,56.0,53.6,41.1,34.6ppm。
4. infrared spectrum: IR (thin film)2926,1596,1450,1427,1335,1223,993,907,704cm-1。
5. High resolution mass spectrometry: HRMS (CI +) Calcd for C36H31N3S2[M++H]:604.1648,Found:604.1644。
From the results, it can be seen that the theoretical mass is 604.1648, while the observed value of the peak found in the actual mass spectrum is 604.1644; the following structure of the product can be determined by combining nuclear magnetic resonance and infrared elemental analysis and standard specific optical rotation:
Example 18
By the use of R1＝OMe,R2＝H,R3＝Me,R4＝Ph2CH,X＝-3-substituted azetidinium quaternary ammonium salts of OTf and R5Mercaptobenzothiazole as 5-Cl as reaction raw material, Na2HPO4The reaction was carried out using 10% chiral phosphoric acid as a base, and the same procedure as described in example 17 above, at 5 ℃ for 96 hours, gave 82.4mg of a colorless oily product in a calculated yield of 88%. The obtained oily product is analyzed by specific optical rotation, High Performance Liquid Chromatography (HPLC) to determine ee value, Nuclear Magnetic Resonance (NMR), infrared and high resolution mass spectrometry. Wherein, the test analysis data is as follows:
specific optical rotation [ alpha ] measured at 1.25 ℃ on D line]D 25:+7.9(c＝1.0,CHCl3)。
2. Determination of ee value by high performance liquid chromatography: chiral column Daicel
An AD-H column; 1% i-PrOH inhexanes; 1.0 mL/min; retention time 7.3min (minor),7.6min (major). The calculated result was 89% ee.
3. Hydrogen spectrum, carbon spectrum of nuclear magnetic resonance analysis:
1H NMR(400MHz,CDCl3)7.84-7.78(m,1H),7.65(d,J＝8.4Hz,1H),7.48-7.38(m,4H),7.34-7.15(m,7H),4.48(s,1H),4.01-3.82(m,1H),3.81-3.70(m,1H),3.45(s,3H),3.47-3.29(m,1H),2.67-2.54(m,2H),2.31(s,3H)ppm.
13C NMR(100MHz,CDCl3)169.8,154.0,142.4,133.5,132.0,128.38,128.36,128.23,128.20(2C),127.0,124.4,121.5(2C),121.2,78.7,76.0,58.0,57.7,41.4,36.3ppm。
4. infrared spectrum: IR (thin film)2928,1428,1067,993,909,798,703cm-1。
5. High resolution mass spectrometry: HRMS (CI +) Calcd for C25H26ClN2OS2[M++H]:469.1175,Found:469.1174。
From the results, it can be seen that the theoretical mass is 469.1175, while the observed value of the peak found in the actual mass spectrum is 469.1174; the following structure of the product can be determined by combining nuclear magnetic resonance and infrared elemental analysis and standard specific optical rotation:
Example 19
By the use of R1＝OBn,R2＝H,R3＝Me,R4＝Ph2CH,X＝-3-substituted azetidinium quaternary ammonium salts of OTf and R5Mercaptobenzothiazole as 5-Cl as reaction raw material, Na2HPO4As a base, with 10% of a chiral phosphoric acid catalyst, according toThe same procedure as described in example 17 above, carried out at 5 ℃ for 96 hours, gave 100.2mg of the product as a colorless oil in a calculated yield of 93%. The obtained oily product is analyzed by specific optical rotation, High Performance Liquid Chromatography (HPLC) to determine ee value, Nuclear Magnetic Resonance (NMR), infrared and high resolution mass spectrometry. Wherein, the test analysis data is as follows:
specific optical rotation [ alpha ] measured at 1.25 ℃ on D line]D 25:-27.5(c＝1.0,CHCl3)。
2. Determination of ee value by high performance liquid chromatography: chiral column Daicel
An AD-H column; 2% i-PrOH inhexanes; 1.0 mL/min; retention time 7.8min (minor),8.7min (major). The calculated result was 91% ee.
3. Hydrogen spectrum, carbon spectrum of nuclear magnetic resonance analysis:
1H NMR(400MHz,CDCl3)7.88-7.81(m,1H),7.65(d,J＝8.8Hz,1H),7.50-7.42(m,4H),7.42-7.18(m,12H),4.71(s,2H),4.50(s,1H),4.06-3.98(m,1H),3.96-3.87(m,1H),3.52(dd,J＝13.2,6.8Hz,1H),2.69(s,2H),2.32(s,3H)ppm.
13C NMR(100MHz,CDCl3)169.7,153.9,142.4,138.1,133.4,132.0,128.38,128.35,128.3(2C),128.18,128.16(2C),127.8,127.6,127.0,124.4,121.5,121.2,76.3,75.9,72.3,58.2,41.5,36.5ppm。
4. infrared spectrum: IR (thin film)2926,1428,1066,991,907,694cm-1。
5. High resolution mass spectrometry: HRMS (CI +) Calcd for C31H30ClN2OS2[M++H]:545.1488,Found:545.1468。
From the results, it can be seen that the theoretical mass is 545.1488, while the observed value of the peak found in the actual mass spectrum is 545.1468; the following structure of the product can be determined by combining nuclear magnetic resonance and infrared elemental analysis and standard specific optical rotation:
Example 20
By the use of R1＝OAllyl,R2＝H,R3＝Me,R4＝Ph2CH,X＝-3-substituted azetidinium quaternary ammonium salts of OTf and R5Mercaptobenzothiazole as 5-Cl as reaction raw material, Na2HPO4The reaction was carried out using 10% chiral phosphoric acid as a base, and the same procedure as described in example 17 above, at 5 ℃ for 96 hours, gave 89.9mg of a colorless oily product, calculated as 91%. The oily product is analyzed by measuring specific optical rotation, and by measuring ee value, nuclear magnetic resonance, infrared and high resolution mass spectrometry by high performance liquid chromatography. Wherein, the test analysis data is as follows:
specific optical rotation [ alpha ] measured at 1.25 ℃ on D line]D 25:-25.1(c＝1.0,CHCl3)。
2. Determination of ee value by high performance liquid chromatography: chiral column Daicel
An OD-H column; 1% i-PrOH inhexanes; 1.0 mL/min; retention time 5.8min (major),11.3min (minor). The calculated result was 88% ee.
3. Hydrogen spectrum, carbon spectrum of nuclear magnetic resonance analysis:
1H NMR(400MHz,CDCl3)7.81(s,1H),7.66(d,J＝8.4Hz,1H),7.44(dd,J＝13.2,7.6Hz,4H),7.34-7.25(m,5H),7.25-7.17(m,2H),5.99-5.85(m,1H),5.32-5.13(m,2H),4.49(s,1H),4.15(d,J＝5.6Hz,2H),4.02-3.83(m,2H),3.44(dd,J＝13.2,6.4Hz,1H),2.72-2.53(m,2H),2.31(s,3H)ppm.
13C NMR(100MHz,CDCl3)169.8,154.0,142.5,142.4,134.7,133.5,132.0,128.39,128.35,128.20,128.17,126.97,126.95,124.4,121.5,121.2,117.1,76.2,75.97,71.3,58.3,41.5,36.6ppm。
4. infrared spectrum: IR (thin film)2849,1427,991,907,695cm-1。
5. High resolution mass spectrometry: HRMS (CI +) Calcd for C27H28ClN2OS2[M++H]:495.1332,Found:495.1315。
From the results, it can be seen that the theoretical mass is 495.1332, while the observed value of the peak found in the actual mass spectrum is 495.1315; the following structure of the product can be determined by combining nuclear magnetic resonance and infrared elemental analysis and standard specific optical rotation:
Example 21
By the use of R1＝OPropargy,R2＝H,R3＝Me,R4＝Ph2CH,X＝-3-substituted azetidinium quaternary ammonium salts of OTf and R5Mercaptobenzothiazole as 5-Cl as reaction raw material, Na2HPO4The reaction was carried out using 10% chiral phosphoric acid as a base, and the same procedure as described in example 17 above, at 5 ℃ for 96 hours, gave 100.1mg of a colorless oily product in a calculated yield of 92%. The oily product is analyzed by measuring specific optical rotation, and by measuring ee value, nuclear magnetic resonance, infrared and high resolution mass spectrometry by high performance liquid chromatography. Wherein, the test analysis data is as follows:
specific optical rotation [ alpha ] measured at 1.25 ℃ on D line]D 25:+4.4(c＝1.0,CHCl3)。
2. Determination of ee value by high performance liquid chromatography: chiral column Daicel
An AD-H column; 1% i-PrOH inhexanes; 1.0 mL/min; the retention time is 9.3min (minor),10.7min (major). The calculated result was 89% ee.
3. Hydrogen spectrum, carbon spectrum of nuclear magnetic resonance analysis:
1H NMR(400MHz,CDCl3)7.80(s,1H),7.65(d,J＝8.4Hz,1H),7.43(dd,J＝12.8,7.6Hz,4H),7.33-7.23(m,5H),7.23-7.15(m,2H),4.49(s,1H),4.35(s,2H),4.15-3.05(m,1H),3.86(dd,J＝13.6,4.4Hz,1H),3.40(dd,J＝13.6,6.4Hz,1H),2.64(d,J＝6.4Hz,2H),2.40(s,1H),2.31(s,3H)ppm.
13C NMR(100MHz,CDCl3)169.5,153.9,142.4,133.5,132.0,128.4,128.2(3C),127.0(2C),124.4,121.5,121.2(2C),79.9,75.9(2C),74.5,58.2,57.6,41.4,36.2ppm。
4. infrared spectrum: IR (thin film)3287,3025,1513,1426,1239,992,908,695cm-1。
5. High resolution mass spectrometry: HRMS (CI +) Calcd for C27H26ClN2OS2[M++H]:493.1175,Found:493.1183。
From the results, it can be seen that the theoretical mass is 493.1175, while the observed value of the peak found in the actual mass spectrum is 493.1183; the following structure of the product can be determined by combining nuclear magnetic resonance and infrared elemental analysis and standard specific optical rotation:
Example 22
By the use of R1＝OBn,R2＝H,R3＝Bn,R4＝Ph2CH,X＝-3-substituted azetidinium quaternary ammonium salts of OTf and R5Mercaptobenzothiazole as 5-Cl as reaction raw material, Na2HPO4The reaction was carried out using 10% chiral phosphoric acid as a base, and the same procedure as described in example 17 above, at 5 ℃ for 96 hours, gave 114.1mg of a colorless oily product in a calculated yield of 92%. The oily product is analyzed by measuring specific optical rotation, and by measuring ee value, nuclear magnetic resonance, infrared and high resolution mass spectrometry by high performance liquid chromatography. Wherein, the test analysis data is as follows:
specific optical rotation [ alpha ] measured at 1.25 ℃ on D line]D 25:-22.8(c＝1.0,CHCl3)。
2. Determination of ee value by high performance liquid chromatography: chiral column Daicel
An OD-H column; 1% i-PrOH inhexanes; 1.0 mL/min; the retention time is 9.8min (minor),12.3min (major). The calculated result was 91% ee.
3. Hydrogen spectrum, carbon spectrum of nuclear magnetic resonance analysis:
1H NMR(400MHz,CDCl3)7.68-7.62(m,2H),7.50(d,J＝8.4Hz,2H),7.48-7.42(m,4H),7.42-7.24(m,15H),5.13(s,1H),4.59(dd,J＝21.2,11.2Hz,2H),3.95-3.84(m,3H),3.67(d,J＝14.0Hz,1H),3.30(dd,J＝14.8,8.0Hz,1H),2.92-2.74(m,2H)ppm.
13C NMR(100MHz,CDCl3)169.4,153.9,140.9,140.1,139.2,138.1,133.4,132.0,129.3,129.1,129.0,128.3(2C),128.19,128.16,127.9,127.6,127.11,127.05,127.0,124.3,121.4,121.1,76.6,72.4,69.6,55.9,53.5,36.5ppm。
4. infrared spectrum: IR (thin film)2862,1708,1427,1065,991,908,694cm-1。
5. High resolution mass spectrometry: HRMS (CI +) Calcd for C37H34ClN2OS2[M++H]:621.1801,Found:621.1813。
From the results, it can be seen that the theoretical mass is 621.1801, while the observed value of the peak found in the actual mass spectrum is 621.1813; the following structure of the product can be determined by combining nuclear magnetic resonance and infrared elemental analysis and standard specific optical rotation:
Example 23
By the use of R1＝CN,R2＝H,R3＝Me,R4＝Ph2CH,X＝-3-substituted azetidinium quaternary ammonium salts of OTf and R5Mercaptobenzothiazole as H as reaction raw material, Na2HPO4The reaction was carried out using 10% chiral phosphoric acid as a base, and the same procedure as described in example 17 above was followed for 24 hours to give 81.5mg of a colorless oily product in a calculated yield of 95%. Analyzing the oily product by measuring specific optical rotation and high performance liquid chromatographySpectral analysis determines ee, nmr, ir and high resolution mass spectra. Wherein, the test analysis data is as follows:
specific optical rotation [ alpha ] measured at 1.25 ℃ on D line]D 25:-17.3(c＝1.0,CHCl3)。
2. Determination of ee value by high performance liquid chromatography: chiral column Daicel
An AD-H column; 5% i-PrOH inhexanes; 1.0 mL/min; the retention time is 9.0min (minor),11.2min (major). The calculated result was 86% ee.
3. Hydrogen spectrum, carbon spectrum of nuclear magnetic resonance analysis:
1H NMR(400MHz,CDCl3)7.81(dd,J＝20.0,8.0Hz,2H),7.55-7.39(m,5H),7.37-7.16(m,7H),4.54(s,1H),3.92(dd,J＝13.6,5.2Hz,1H),3.65-3.52(m,1H),3.29(dd,J＝13.6,8.8Hz,1H),2.92-2.72(m,2H),2.36(s,3H)ppm.
13C NMR(100MHz,CDCl3)164.9,152.9,142.0,141.9,135.4,128.7(2C),128.2,128.1,127.4,126.2(2C),124.6,121.6,121.2,120.4,75.5,56.1,40.6,32.7,31.8ppm。
4. infrared spectrum: IR (thin film)2926,2237,1597,1446,1220,997,938,704cm-1。
5. High resolution mass spectrometry: HRMS (CI +) Calcd for C25H22N3S2[M+-H]:428.1250,Found:428.1262。
From the results, it can be seen that the theoretical mass is 428.1250, while the observed value of the peak found in the actual mass spectrum is 428.1262; the following structure of the product can be determined by combining nuclear magnetic resonance and infrared elemental analysis and standard specific optical rotation:
Example 24
By the use of R1＝CN,R2＝H,R3＝Me,R4＝Ph2CH,X＝-3-substituted azetidinium quaternary ammonium salts of OTf and R5Mercaptobenzothiazole as 5-Cl as reaction raw material, Na2HPO4The reaction was carried out using 10% chiral phosphoric acid as a base, and the same procedure as described in example 17 above, for 24 hours, gave 86.1mg of a colorless oily product in a calculated yield of 93%. The oily product is analyzed by measuring specific optical rotation, and by measuring ee value, nuclear magnetic resonance, infrared and high resolution mass spectrometry by high performance liquid chromatography. Wherein, the test analysis data is as follows:
specific optical rotation [ alpha ] measured at 1.25 ℃ on D line]D 25:-50.9(c＝1.0,CHCl3)。
2. Determination of ee value by high performance liquid chromatography: chiral column Daicel
An AD-H column; 5% i-PrOH inhexanes; 1.0 mL/min; retention time 7.3min (minor),13.3min (major). The calculated result was 87% ee.
3. Hydrogen spectrum, carbon spectrum of nuclear magnetic resonance analysis:
1H NMR(400MHz,CDCl3)7.77-7.74(m,1H),7.66(d,J＝8.8Hz,1H),7.50-7.40(m,4H),7.35-7.17(m,7H),4.53(s,1H),3.92(dd,J＝13.2,5.2Hz,1H),3.59-3.51(m,1H),3.28(dd,J＝13.6,8.8Hz,1H),2.88-2.72(m,2H),2.35(s,3H)ppm.
13C NMR(100MHz,CDCl3)167.1,153.5,141.8(2C),133.5,128.6(2C),128.1,128.0,127.3,124.9(2C),121.7,121.4(2C),120.1,75.4,55.9,40.5,32.6,31.7ppm。
4. infrared spectrum: IR (thin film)2925,2242,1547,1428,1296,1067,996,909,705cm-1。
5. High resolution mass spectrometry: HRMS (CI +) C25H21ClN3S2[M+-H]:462.0860,Found:462.0872。
From the results, it can be seen that the theoretical mass is 462.0860, while the observed value of the peak found in the actual mass spectrum is 462.0872; the following structure of the product can be determined by combining nuclear magnetic resonance and infrared elemental analysis and standard specific optical rotation:
Example 25
By the use of R1＝OBn,R2＝Vinyl,R3＝Me,R4＝Ph2CH,X＝-3-substituted azetidinium quaternary ammonium salts of OTf and R5Mercaptobenzothiazole as 5-Cl as reaction raw material, Na2HPO4The reaction was carried out using 10% chiral phosphoric acid as a base, and the same procedure as described in example 17 above was followed for 96 hours to give 108.3mg of a colorless oily product in a calculated yield of 95%. The oily product is analyzed by measuring specific optical rotation, and by measuring ee value, nuclear magnetic resonance, infrared and high resolution mass spectrometry by high performance liquid chromatography. Wherein, the test analysis data is as follows:
specific optical rotation [ alpha ] measured at 1.25 ℃ on D line]D 25:-21.3(c＝1.0,CHCl3)。
2. Determination of ee value by high performance liquid chromatography: chiral column Daicel
An AD-H column; 1% i-PrOH inhexanes; 1.0 mL/min; retention time 12.8min (major),13.6min (minor). The calculated result was 87% ee.
3. Hydrogen spectrum, carbon spectrum of nuclear magnetic resonance analysis:
1H NMR(400MHz,CDCl3)7.82(s,1H),7.63(d,J＝8.4Hz,1H),7.39(d,J＝7.6Hz,4H),7.35-7.19(m,12H),6.02(dd,J＝26.4,12.8Hz,2H),5.44-5.34(m,2H),4.82(s,1H),4.51(s,2H),4.09(dd,J＝13.2,6.8Hz,1H),2.90(d,J＝14.0Hz,1H),2.80(d,J＝14.0Hz,1H),2.38(s,3H)ppm；
13C NMR(100MHz,CDCl3)170.5,153.9,141.6,139.2(2C),138.5,133.5,131.9,128.8,128.7,128.20,128.16,128.1,127.2(2C),126.9,126.8,124.3,121.5,121.2,117.2,80.7,74.9,64.8,61.4,41.1,38.1ppm。
4. infrared spectrum: IR (thin)film)2841,2797,1426,990,906,694cm-1。
5. High resolution mass spectrometry: HRMS (CI +) C33H32ClN2OS2[M+-H]:569.1483,Found:569.1495.。
From the results, it can be seen that the theoretical mass is 569.1483, while the observed value of the peak found in the actual mass spectrum is 569.1495; the following structure of the product can be determined by combining nuclear magnetic resonance and infrared elemental analysis and standard specific optical rotation:
Example 26
By the use of R1＝Allyl,R2＝CN,R3＝Me,R4＝Ph2CH,X＝-3-substituted azetidinium quaternary ammonium salts of OTf and R5Mercaptobenzothiazole as 6-OEt as reaction raw material, Na2HPO4The reaction was carried out using 10% chiral phosphoric acid as a base, and the same procedure as described in example 17 above was followed for 96 hours to give 84.2mg of a colorless oily product in a calculated yield of 82%. The oily product is analyzed by measuring specific optical rotation, and by measuring ee value, nuclear magnetic resonance, infrared and high resolution mass spectrometry by high performance liquid chromatography. Wherein, the test analysis data is as follows:
specific optical rotation [ alpha ] measured at 1.25 ℃ on D line]D 25:-4.2(c＝1.0,CHCl3)。
2. Determination of ee value by high performance liquid chromatography: chiral column Daicel
An IC column; 10% i-PrOH inhexanes; 1.0 mL/min; the retention time is 11.3min (major) and 13.2min (minor). The calculated result was 75% ee.
3. Hydrogen spectrum, carbon spectrum of nuclear magnetic resonance analysis:
1H NMR(400MHz,CDCl3)7.72(d,J＝8.8Hz,1H),7.38-7.20(m,11H),7.03(d,J＝8.8Hz,1H),5.93-5.78(m,1H),5.25-5.13(m,2H),4.77(s,1H),4.08(dd,J＝14.0,6.8Hz,2H),3.87(d,J＝13.2Hz,1H),3.77(d,J＝13.2Hz,1H),2.81(s,2H),2.58-2.48(m,1H),2.45(s,3H),2.46-2.38(m,1H),1.46(t,J＝7.2Hz,3H)ppm；
13C NMR(100MHz,CDCl3)162.0,156.5,147.2,140.7,140.7,136.8,131.1,128.7,128.6,128.3(2C),127.1(2C),122.2,122.1,120.9,115.4,104.8,74.6,64.1,60.2,42.7,40.8,39.6,37.6,14.8ppm。
4. infrared spectrum: IR (thin film)2979,2233,1599,1446,1221,995,910,820,700cm-1。
5. High resolution mass spectrometry: HRMS (CI +) C30H30N3OS2[M+-H]:512.1825,Found:512.1851。
From the results, it can be seen that the theoretical mass is 512.1825, while the observed value of the peak found in the actual mass spectrum is 512.1851; the following structure of the product can be determined by combining nuclear magnetic resonance and infrared elemental analysis and standard specific optical rotation:
Example 27
The compound obtained in example 19 was used to prepare a β -aminosulfone product according to the following reaction equation:
the implementation steps are as follows: the product of example 19 as a reaction starting material (109.1mg,0.2mmol, 91% ee) was dissolved in dry methanol (1mL) and CF was added3CO2H (0.1mL,1.3mmol), stirring at room temperature for 15 minutes, then adding DCM (1mL) to dilute and cool to 0 deg.C, and slowly dropping (NH)4)6Mo7O24·4H2O (247.2mg,0.2mmol) and 35% aq H2O2(2.0mL,23.3mmol) of a mixed ice-water cooled solution. After stirring at room temperature for 5 hours, a saturated aqueous sodium bicarbonate solution (10mL) was added theretoQuenching is carried out, and stirring is carried out rapidly for half an hour. Extraction with dichloromethane (20 mL. times.3), washing with saturated brine (30mL), drying over anhydrous sodium sulfate, and concentration gave a pale yellow solid (103.9mg, 90% yield) which was pure enough to be used in the next step. The yellow solid product is analyzed by means of nuclear magnetic resonance, infrared and high-resolution mass spectrometry. Wherein, the test analysis data is as follows:
1. hydrogen spectrum, carbon spectrum of nuclear magnetic resonance analysis:
1H NMR(400MHz,CDCl3)8.11-8.07(m,1H),7.70(d,J＝8.8Hz,1H),7.45(dd,J＝8.8,2.0Hz,1H),7.39-7.29(m,4H),7.29-7.24(m,4H),7.21(t,J＝7.2Hz,2H),7.09(t,J＝7.2Hz,1H),7.02(t,J＝7.6Hz,2H),6.86(d,J＝7.6Hz,2H),4.55(d,J＝11.2Hz,1H),4.40-4.32(m,2H),4.31-4.25(m,1H),4.06(d,J＝15.2Hz,1H),3.92(dd,J＝15.2,9.6Hz,1H),2.63-2.48(m,2H),2.23(s,3H)；
13C NMR(100MHz,CDCl3)168.6,153.2,142.1,142.0,137.1,134.8,133.5,128.6,128.5,128.2,128.01,127.96,127.8,127.3,127.20,127.17,126.8,124.8,122.9,76.1,73.2,71.9,58.3,56.9,41.5。
2. infrared spectrum: IR (thin film)3027,2852,1587,1513,1324,1143,904,925,696cm-1。
3. High resolution mass spectrometry: HRMS m/z (LD +) Calcd for C31H30ClN2O3S2[M++H]:577.1386,found:577.13992。
From the results, it can be seen that the theoretical mass is 577.1386, while the observed value of the peak found in the actual mass spectrum is 577.13992; by combining nuclear magnetic resonance and infrared elemental analysis, the structure of the product can be determined as follows:
Example 28
The oxidation step of example 27 gave the corresponding sulfone-based product, which was then subjected to the following equation to produce the aminoolefin product:
the implementation steps are as follows: the starting material, example 27 (103.9mg,0.18mmol), was dissolved in THF (tetrahydrofuran, 2mL) at-78 deg.C, then KHMDS (0.8mL,0.5M in toluene,0.4mmol) was slowly added dropwise. Half an hour later, a solution of benzaldehyde (42.4mg,0.4mmol) in THF (0.5mL) was slowly added dropwise, stirring was continued for an additional 1 hour, then warmed to room temperature and stirred overnight. Adding saturated NH into ice water bath4The reaction was quenched with Cl solution (10 mL). The temperature was raised to normal temperature, extracted with ethyl acetate (20 mL. times.3), dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel column chromatography to give a pale yellow oily liquid product (64.2mg, 82% yield). The oily product is analyzed by measuring specific optical rotation, and by measuring ee value, nuclear magnetic resonance, infrared and high resolution mass spectrometry by high performance liquid chromatography. Wherein, the test analysis data is as follows:
specific optical rotation [ alpha ] measured at 1.25 ℃ on D line]D 25:+48.7(c＝1.0,CHCl3)。
2. Determination of ee value by high performance liquid chromatography: chiral column Daicel
An AD-H column; 1% i-PrOH inhexanes; 1.0 mL/min; retention time 5.8min (minor),7.1min (major). The calculated result was 90% ee.
3. Hydrogen spectrum, carbon spectrum of nuclear magnetic resonance analysis:
1H NMR(400MHz,CDCl3)7.52-7.39(m,12H),7.39-7.28(m,6H),7.28-7.22(m,2H),6.64(d,J＝16.0Hz,1H),6.26-6.16(m,1H),4.75(d,J＝12.0Hz,1H),4.60-4.52(m,2H),4.28-4.21(m,1H),2.87-2.70(m,2H),2.36(s,3H)；
13C NMR(100MHz,CDCl3)142.8,142.7,138.7,136.7,132.2(2C),129.6,128.6(2C),128.3(2C),128.2(2C),127.6,127.4,126.8,126.4(2C),78.7,75.5,70.3,59.8,41.5。
4. infrared spectrum: IR (thin film)2959,2846,1598,1451,1247,1069,925,692cm-1。
5. High resolution mass spectrometry: HRMS m/z (CI) Calcd for C31H32NO[M++H]:434.2484,found:434.2473。
From the results, it can be seen that the theoretical mass is 434.2484, while the observed value of the peak found in the actual mass spectrum is 434.2473; the following structure of the product can be determined by combining nuclear magnetic resonance and infrared elemental analysis and standard specific optical rotation:
Example 29:
the product from example 7 was used to prepare a debiphenylmethyl and Boc protected product according to the following equation:
the implementation steps are as follows: the reaction starting material, i.e., the product obtained in example 7 (115.0mg,0.2mmol, 95% ee) was dissolved in trifluoroacetic acid (2.5mL) at room temperature, and Et was added thereto3After SiH (0.16mL,1.0mmol), it was stirred at 85 ℃ for 12 hours. Then cooled to room temperature and saturated Na was added2CO3The reaction was quenched with solution (25mL), extracted with ethyl acetate (20 mL. times.3), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was dissolved in dichloromethane (2mL) and then N, N-lutidine (12.2mg,0.02mmol) and Boc were added sequentially2(65.6mg,0.3 mmol). The reaction mixture was stirred at room temperature for 3 hours, concentrated, and subjected to silica gel column chromatography to obtain a colorless oily liquid product (73.2mg, 72% yield). The oily product is analyzed by measuring specific optical rotation, and by measuring ee value, nuclear magnetic resonance, infrared and high resolution mass spectrometry by high performance liquid chromatography. Wherein, the test analysis data is as follows:
specific optical rotation [ alpha ] measured at 1.25 ℃ on D line]D 25:-75.9(c＝1.0,CHCl3)。
2. Determination of ee value by high performance liquid chromatography: chiral column Daicel
An IC column; 10% i-PrOH inhexanes; 1.0 mL/min; retention time 15.2min (major),17.1min (minor). The calculated result was 96% ee.
3. Hydrogen spectrum, carbon spectrum of nuclear magnetic resonance analysis:
1H NMR(400MHz,CDCl3)7.84-7.64(m,5H),7.48-7.33(m,3H),7.20-7.16(m,1H),7.00(dd,J＝8.8,2.4Hz,1H),4.06(q,J＝6.8Hz,2H),4.03-3.79(m,2H),3.64-3.41(m,3H),2.78(s,3H),1.48-1.37(m,12H)；
13C NMR(100MHz,CDCl3)163.1,156.4,155.5,147.5,138.2,136.5,133.4,132.7,128.4,127.7,127.6,126.9,126.2,125.8,125.6,121.9,115.3,104.8,79.7,64.1,54.4,44.9,36.8,34.9,28.3,14.8。
4. infrared spectrum: IR (thin film)2976,1686,1599,1446,1221,1160,997,817,729cm-1。
5. High resolution mass spectrometry: HRMS m/z (LD +) Calcd for C28H33N2O3S2[M++H]:509.1933,found:509.1908。
From the results, it can be seen that the theoretical mass is 509.1933, while the observed value of the peak found in the actual mass spectrum is 509.1908; the following structure of the product can be determined by combining nuclear magnetic resonance and infrared elemental analysis and standard specific optical rotation:
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (4)
1. A method for preparing chiral beta-amino derivatives is characterized by comprising the following steps:
providing azetidine quaternary ammonium salt shown as a formula I and nucleophilic reagent shown as a formula V;
dissolving the azetidine quaternary ammonium salt and the nucleophilic reagent in a first organic solvent, and performing asymmetric ring-opening reaction under the conditions of inorganic base and a catalyst shown as a formula III to obtain a chiral beta-amino derivative shown as a formula VI;
wherein R is1Is any one of benzene ring or substituted benzene ring, condensed ring or substituted condensed ring, thiophene, alkenyl, benzyl, cyano, ester group, amide and ether, the substituted group of the substituted benzene ring and the substituted condensed ring is one of halogen, methyl, methoxy, trifluoromethoxy and trifluoromethyl, and R is2Is any one of alkenyl, cyano and hydrogen atom, R3Is diphenylmethyl, R4Is any one of methyl and benzyl, R5Is any one of hydrogen atom, halogen, methyl, methoxyl and ethoxyl; x is any one of trifluoromethanesulfonic acid anion and tetrafluoroborate anion; ar (Ar)1And Ar2Is any one of phenyl, naphthyl, 9-phenanthryl, 9-anthryl, 1-pyrenyl, 3, 5-ditrifluoromethylphenyl and 2,4, 6-tricyclohexylphenyl; the inorganic base is Na2HPO4、Na3PO4、K2HPO4、K3PO4、Na2CO3、NaHCO3And K2CO3The first solvent is at least one of n-hexane, dichloromethane, 1, 2-dichloroethane, chloroform, diethyl ether, toluene, fluorobenzene and trifluorotoluene.
2. The method of claim 1, wherein the inorganic base is 200% of the molar amount of azetidine quaternary ammonium salt; and/or
The catalyst is 10% of the molar amount of the azetidine quaternary ammonium salt; and/or
The temperature of the asymmetric ring-opening reaction is 5-30 ℃.
3. The method of claim 1, wherein the azetidine quaternary ammonium salt is dissolved in the first organic solvent to a concentration of 0.02 to 0.2 mol/L.
4. A method for preparing an aminoolefin derivative, comprising the steps of:
obtaining a compound of formula VI using the preparation method of claim 1;
dissolving a compound shown as a formula VI in a second organic solvent, and then carrying out oxidation reaction with hydrogen peroxide to obtain an intermediate shown as a formula VII, wherein CF is added in the oxidation reaction process3CO2H and (NH)4)6Mo7O24·4H2O；
Dissolving the intermediate shown in the formula VII in a third organic solvent, and then sequentially adding hexamethyldisilazane-based amino potassium and benzaldehyde for reaction to obtain the amino olefin derivative shown in the formula VIII.
Wherein, Ar in the formula VIII3Is phenyl.
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