CN118666838A - Asymmetric synthesis method of 1, 1-disubstituted-tetrahydro-beta-carboline derivative - Google Patents
Asymmetric synthesis method of 1, 1-disubstituted-tetrahydro-beta-carboline derivative Download PDFInfo
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- tetrahydro
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- -1 1, 1-disubstituted-tetrahydro-beta-carboline Chemical class 0.000 title claims abstract description 44
- 238000000034 method Methods 0.000 title claims abstract description 23
- 238000011914 asymmetric synthesis Methods 0.000 title claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 50
- 239000003446 ligand Substances 0.000 claims abstract description 21
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims abstract description 18
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000012298 atmosphere Substances 0.000 claims abstract description 5
- 238000000746 purification Methods 0.000 claims abstract description 3
- 238000000926 separation method Methods 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 72
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 44
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 42
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 30
- 229940125904 compound 1 Drugs 0.000 claims description 27
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 24
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 22
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 22
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 12
- 239000012074 organic phase Substances 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- 125000006281 4-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)C([H])([H])* 0.000 claims description 2
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 238000004440 column chromatography Methods 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 4
- 229960003280 cupric chloride Drugs 0.000 abstract description 2
- 231100000252 nontoxic Toxicity 0.000 abstract description 2
- 230000003000 nontoxic effect Effects 0.000 abstract description 2
- 238000006555 catalytic reaction Methods 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 20
- 238000004090 dissolution Methods 0.000 description 11
- 238000001308 synthesis method Methods 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 235000019270 ammonium chloride Nutrition 0.000 description 10
- 239000012043 crude product Substances 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- 230000014759 maintenance of location Effects 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- 239000003208 petroleum Substances 0.000 description 10
- 229920006395 saturated elastomer Polymers 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 230000002194 synthesizing effect Effects 0.000 description 10
- 238000001228 spectrum Methods 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 229930014626 natural product Natural products 0.000 description 7
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- APJYDQYYACXCRM-UHFFFAOYSA-N tryptamine Chemical class C1=CC=C2C(CCN)=CNC2=C1 APJYDQYYACXCRM-UHFFFAOYSA-N 0.000 description 3
- RIZDDRXJJMJQIS-BFUOFWGJSA-N 1-[(1R,15R)-3,13-diazapentacyclo[13.3.1.01,13.02,10.04,9]nonadeca-2(10),4,6,8,17-pentaen-17-yl]ethanone Chemical compound CC(=O)C1=C[C@@]23C[C@H](CN2CCc2c3[nH]c3ccccc23)C1 RIZDDRXJJMJQIS-BFUOFWGJSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229930005303 indole alkaloid Natural products 0.000 description 2
- 150000002475 indoles Chemical class 0.000 description 2
- CFTOTSJVQRFXOF-UHFFFAOYSA-N 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole Chemical class N1C2=CC=CC=C2C2=C1CNCC2 CFTOTSJVQRFXOF-UHFFFAOYSA-N 0.000 description 1
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- TYFNYCCYPLVLLL-UHFFFAOYSA-N Misrhybridine Natural products COC1CC2(CCC13Cc4[nH]c5cc(OC)c(OC)cc5c4CN3)CC6N(C)CCc7cc(OC)c(O)c2c67 TYFNYCCYPLVLLL-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
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- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses an asymmetric synthesis method of a1, 1-disubstituted-tetrahydro-beta-carboline derivative, belonging to the technical field of organic synthesis. The method comprises the following steps: in a reactor, under the inert atmosphere, the 1, 1-diol-tetrahydro-beta-carboline compound reacts with benzoyl chloride under the catalysis of chiral ligand and cupric chloride, and subsequent separation and purification are carried out after the reaction is finished, so that the 1, 1-disubstituted-tetrahydro-beta-carboline derivative can be obtained. The method has the advantages of simple steps, safe operation, nontoxic and easily obtained raw materials, simple and feasible whole process and small pollution, and accords with the concept of green chemistry.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to an asymmetric synthesis method of a1, 1-disubstituted-tetrahydro-beta-carboline derivative.
Background
1, 1-Disubstituted-tetrahydro- β -carboline backbone structures, with an aza-quaternary carbon chiral center at the C1 position, are widely found in various biologically and pharmaceutically active natural products and are often used as synthetic raw materials for indole alkaloids (Y.Li, C.Wang, Z.Ma, K.Zhang, X.T.Xu, org.Lett.2020,22, 8589-8592). Starting from this class of compounds, various indole alkaloids with different biological activities, such as ALSTRATINE A, arbornamine, tabertinggine, roemeridine, PEHARMALINE A, peganumine A, voacafricine, etc., can be synthesized. More importantly, the chiral enantiomer may show distinct pharmacological, pharmacokinetic, metabolic and toxicological activities and the like in organisms, so that the synthesis of the optically pure 1, 1-disubstituted-tetrahydro-beta-carboline compound has very important significance. As for the report of tryptamine derivatives, the former report has few examples, and only in 2018, the Snyder subject group (P.Gan; J.Pitzen; P.Qu; S.A.Snyder, J.Am.Chem.Soc.2018,140,919-925) reports that chiral oxazoline ligand and cupric chloride catalyze 2- (2 ',2' -diol) tryptamine derivatives to react with benzoyl chloride to synthesize 2- (2 ',2' -disubstituted) tryptamine derivatives, but the product synthesized by the method needs to be converted by one step to obtain 1, 1-disubstituted-tetrahydro-beta-carboline derivatives, which greatly influences the total synthesis efficiency of natural products.
In view of the diversity of natural products and drug molecules, the development of a novel asymmetric synthesis method for 1, 1-disubstituted-tetrahydro-beta-carboline derivatives remains an important research direction.
Disclosure of Invention
In order to solve the defects and the shortcomings existing in the prior art, the invention aims to provide a method for asymmetric synthesis of an aza-quaternary carbon chiral center, and more particularly provides an asymmetric synthesis method of a1, 1-disubstituted-tetrahydro-beta-carboline derivative.
The invention is realized by the following technical scheme:
An asymmetric synthesis method of a1, 1-disubstituted-tetrahydro-beta-carboline derivative comprises the following steps:
(1) In a reactor, the chiral ligand and the copper chloride are pumped to be dry at room temperature to remove the water of a reaction system, and then added with an organic solvent for dissolution; adding an organic solvent containing a compound 1 under an inert atmosphere, cooling, and sequentially adding benzoyl chloride and triethylamine to react;
(2) After the reaction is finished, the reaction liquid is separated and purified, and the 1, 1-disubstituted-tetrahydro-beta-carboline derivative can be obtained.
The structural formula of the compound 1 is as follows:
Wherein R 1 is one of methoxy, methyl, fluorine, bromine and hydrogen, and R 2 is one of benzyl, 4-bromobenzyl and 4-methoxybenzyl.
Further, the organic solvent in the step (1) is one of methanol, ethanol, N-propanol, isopropanol, tert-butanol, acetonitrile, ethyl acetate, dichloromethane, dichloroethane, chloroform, tetrahydrofuran, acetone, toluene, N-dimethylformamide, dimethyl sulfoxide, 2-methyltetrahydrofuran, diethyl ether, tert-butyldimethyl ether and 1, 4-dioxane.
Further, the inert atmosphere in the step (1) is a nitrogen atmosphere.
Further, the chiral ligand in the step (1) has the following structural general formula:
Wherein R 3 is one of benzyl, phenyl, isopropyl, sec-butyl, tert-butyl, n-butyl, benzocyclopentyl, 2- (methylene) naphthyl, and 1- (methylene) naphthyl, R 4 is one of methyl, ethyl, n-butyl, tert-butyl, phenyl, and hydrogen atoms, and R 5 is one of methyl, cyclopropyl (n=0), cyclopentyl (n=2), cyclohexyl (n=3), and cycloheptyl (n=4).
Further, the temperature of the step (1) is reduced to-78 ℃, and the reaction time is 12-120 h at the temperature.
Further, the molar ratio of the compound 1 to the chiral ligand in the step (1) is 1:0.1-1:1.
Further, the molar ratio of the compound 1 to the copper chloride in the step (1) is 1:0.1-1:1.
Further, the molar ratio of the compound 1 to the benzoyl chloride in the step (1) is 1:1.1-1:10.
Further, the molar ratio of the compound 1 to the triethylamine in the step (1) is 1:1.1-1:10.
Further, the specific steps of separation and purification in the step (2) are as follows: the saturated ammonium chloride aqueous solution is quenched, extracted by ethyl acetate, backwashed by saturated sodium chloride solution, dried by anhydrous sodium sulfate, filtered, and the organic phase is concentrated, and separated and purified by column chromatography.
Further, the product 1, 1-disubstituted-tetrahydro-beta-carboline derivative obtained by the reaction is one of a compound (R)-2((R)-(2-benzyl-1-(hydroxymethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)methyl benzoate), and a compound (S)-2((S)-(2-benzyl-1-(hydroxymethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)methyl benzoate), and the structural formulas of the compound (R)-2((R)-(2-benzyl-1-(hydroxymethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)methyl benzoate), and the compound (S)-2((S)-(2-benzyl-1-(hydroxymethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)methyl benzoate) are respectively as follows:
wherein Bn is benzyl and Bz is benzoyl.
The reaction equation of the synthesis method of the invention is as follows:
compared with the prior art, the invention has the following advantages:
(1) The invention takes the tetrahydro-beta-carboline derivative as the raw material, is nontoxic, low in cost and easy to obtain, and has simple synthesis steps and safe operation.
(2) The 1, 1-disubstituted-tetrahydro-beta-carboline derivative synthesized by the invention contains an aza quaternary carbon chiral center, is necessary in quite a plurality of natural products, and can be further subjected to derivatization of various functional group conversion and cyclization reactions.
(3) Compared with the steps disclosed in the prior art, the method provided by the invention has the advantages that the reaction yield is obviously improved, the product yield can reach more than 90%, and the synthesis efficiency of the subsequent natural products is obviously improved.
(4) The asymmetric synthesis of the 1, 1-disubstituted-tetrahydro-beta-carboline derivative can be realized after chiral ligand is added, the optically pure 1, 1-disubstituted-tetrahydro-beta-carboline derivative can be obtained, the optically pure 1, 1-disubstituted-tetrahydro-beta-carboline derivative can be applied to the synthesis of a natural product Arbornamine, and the natural product has better anti-inflammatory activity compared with indometacin.
Drawings
FIG. 1 is a hydrogen spectrum of compound 1 of the present invention;
FIG. 2 is a carbon spectrum of compound 1 of the present invention;
FIG. 3 is a hydrogen spectrum of the compound (S) -2 and the compound (R) -2 of the present invention;
FIG. 4 is a graph showing the carbon spectra of the compound (S) -2 and the compound (R) -2 of the present invention.
Detailed Description
The invention is further described below with reference to specific examples and figures, but embodiments of the invention are not limited thereto.
The experimental methods in the following examples are conventional methods unless otherwise specified. The raw materials, reagent materials and the like used in the examples described below are commercially available products unless otherwise specified. Chiral ligands L1 to L8 are all commercially available from Daicel or Innock (innochem) reagent company.
The products prepared in the following examples were all stored below-18 ℃.
Example 1
The synthesis method for asymmetrically synthesizing the 1, 1-disubstituted-tetrahydro-beta-carboline derivative comprises the following steps:
Ligand L1 (10.0 mg,0.03 mmol) and copper chloride (4 mg,0.03 mmol) were weighed into a 40mL reaction flask, evacuated with a vacuum pump for 2h, then nitrogen was introduced, anhydrous tetrahydrofuran (3 mL) was added, and stirring was performed at room temperature for 4h until complete dissolution. A solution of Compound 1 (96.6 mg,0.3 mmol) in 3mL of tetrahydrofuran was then added to the reaction flask. Cooled to-78 ℃, benzoyl chloride (52 μl,0.45 mmol) and triethylamine (46 μl,0.33 mmol) were added sequentially, and the reaction was maintained at-78 ℃ for 12h. The reaction was quenched with saturated aqueous ammonium chloride at-78 ℃, extracted three times with ethyl acetate, the organic phases were combined, backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was isolated using a flash preparative silica gel column (petroleum ether/ethyl acetate=5:1) to give compound (S) -2 (white solid, 39.6mg, yield: 31%, ee% (enantiomeric excess): 30%).
The synthetic route is as follows:
HPLC conditions: OD-H column (n-hexane/isopropanol=90/10, flow rate 1.0 ml/min), retention time: t R =12.8 min (primary), t R =22.1 min (secondary).
Example 2
The synthesis method for asymmetrically synthesizing the 1, 1-disubstituted-tetrahydro-beta-carboline derivative comprises the following steps:
Ligand L2 (10.9 mg,0.03 mmol) and copper chloride (4 mg,0.03 mmol) were weighed into a 40mL reaction flask, evacuated with a vacuum pump for 2h, then nitrogen was introduced, anhydrous tetrahydrofuran (3 mL) was added, and stirring was performed at room temperature for 4h until complete dissolution. A solution of Compound 1 (96.6 mg,0.3 mmol) in 3mL of tetrahydrofuran was then added to the reaction flask. Cooled to-78 ℃, benzoyl chloride (52 μl,0.45 mmol) and triethylamine (46 μl,0.33 mmol) were added sequentially, and the reaction was maintained at-78 ℃ for 12h. The reaction was quenched with saturated aqueous ammonium chloride at-78 ℃, extracted three times with ethyl acetate, the organic phases were combined, backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was isolated using a flash preparative silica gel column (petroleum ether/ethyl acetate=5:1) to give compound (S) -2 (white solid, 102.2mg, yield: 80%, ee% (enantiomeric excess): 76%).
The synthetic route is as follows:
HPLC conditions: OD-H column (n-hexane/isopropanol=90/10, flow rate 1.0 ml/min), retention time: t R =12.8 min (primary), t R =22.1 min (secondary).
Example 3
The synthesis method for asymmetrically synthesizing the 1, 1-disubstituted-tetrahydro-beta-carboline derivative comprises the following steps:
Ligand L3 (8.8 mg,0.03 mmol) and copper chloride (4 mg,0.03 mmol) were weighed into a 40mL reaction flask, evacuated with a vacuum pump for 2h, then nitrogen was added, anhydrous tetrahydrofuran (3 mL) was added, and stirring was performed at room temperature for 4h until complete dissolution. A solution of Compound 1 (96.6 mg,0.3 mmol) in 3mL of tetrahydrofuran was then added to the reaction flask. Cooled to-78 ℃, benzoyl chloride (52 μl,0.45 mmol) and triethylamine (46 μl,0.33 mmol) were added sequentially, and the reaction was maintained at-78 ℃ for 12h. The reaction was quenched with saturated aqueous ammonium chloride at-78 ℃, extracted three times with ethyl acetate, the organic phases were combined, backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was isolated using a flash preparative silica gel column (petroleum ether/ethyl acetate=5:1) to give compound (S) -2 (white solid, 29.4mg, yield: 23%, ee% (enantiomeric excess): 4%).
The synthetic route is as follows:
HPLC conditions: OD-H column (n-hexane/isopropanol=90/10, flow rate 1.0 ml/min), retention time: t R =12.8 min (primary), t R =22.1 min (secondary).
Example 4
The synthesis method for asymmetrically synthesizing the 1, 1-disubstituted-tetrahydro-beta-carboline derivative comprises the following steps:
ligand L4 (11.7 mg,0.03 mmol) and copper chloride (4 mg,0.03 mmol) were weighed into a 40mL reaction flask, evacuated with a vacuum pump for 2h, then nitrogen was added, anhydrous tetrahydrofuran (3 mL) was added, and stirring was performed at room temperature for 4h until complete dissolution. A solution of Compound 1 (96.6 mg,0.3 mmol) in 3mL of tetrahydrofuran was then added to the reaction flask. Cooled to-78 ℃, benzoyl chloride (52 μl,0.45 mmol) and triethylamine (46 μl,0.33 mmol) were added sequentially, and the reaction was maintained at-78 ℃ for 12h. The reaction was quenched with saturated aqueous ammonium chloride at-78 ℃, extracted three times with ethyl acetate, the organic phases were combined, backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was isolated using a flash preparative silica gel column (petroleum ether/ethyl acetate=5:1) to give compound (S) -2 (white solid, 117.8mg, yield 92%, ee% (enantiomeric excess): 79%).
The synthetic route is as follows:
HPLC conditions: OD-H column (n-hexane/isopropanol=90/10, flow rate 1.0 ml/min), retention time: t R =12.8 min (primary), t R =22.1 min (secondary).
Example 5
The synthesis method for asymmetrically synthesizing the 1, 1-disubstituted-tetrahydro-beta-carboline derivative comprises the following steps:
Ligand L5 (12.5 mg,0.03 mmol) and copper chloride (4 mg,0.03 mmol) were weighed into a 40mL reaction flask, evacuated with a vacuum pump for 2h, then nitrogen was added, anhydrous tetrahydrofuran (3 mL) was added, and stirring was performed at room temperature for 4h until complete dissolution. A solution of Compound 1 (96.6 mg,0.3 mmol) in 3mL of tetrahydrofuran was then added to the reaction flask. Cooled to-78 ℃, benzoyl chloride (52 μl,0.45 mmol) and triethylamine (46 μl,0.33 mmol) were added sequentially, and the reaction was maintained at-78 ℃ for 12h. The reaction was quenched with saturated aqueous ammonium chloride at-78 ℃, extracted three times with ethyl acetate, the organic phases were combined, backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was isolated using a flash preparative silica gel column (petroleum ether/ethyl acetate=5:1) to give compound (S) -2 (white solid, 107.4mg, yield: 84%, ee% (enantiomeric excess): 72%).
The synthetic route is as follows:
HPLC conditions: OD-H column (n-hexane/isopropanol=90/10, flow rate 1.0 ml/min), retention time: t R =12.8 min (primary), t R =22.1 min (secondary).
Example 6
The synthesis method for asymmetrically synthesizing the 1, 1-disubstituted-tetrahydro-beta-carboline derivative comprises the following steps:
Ligand L6 (10.8 mg,0.03 mmol) and copper chloride (4 mg,0.03 mmol) were weighed into a 40mL reaction flask, evacuated with a vacuum pump for 2h, then nitrogen was added, anhydrous tetrahydrofuran (3 mL) was added, and stirring was performed at room temperature for 4h until complete dissolution. A solution of Compound 1 (96.6 mg,0.3 mmol) in 3mL of tetrahydrofuran was then added to the reaction flask. Cooled to-78 ℃, benzoyl chloride (52 μl,0.45 mmol) and triethylamine (46 μl,0.33 mmol) were added sequentially, and the reaction was maintained at-78 ℃ for 12h. The reaction was quenched with saturated aqueous ammonium chloride at-78 ℃, extracted three times with ethyl acetate, the organic phases were combined, backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was isolated using a flash preparative silica gel column (petroleum ether/ethyl acetate=5:1) to give compound (R) -2 (white solid, 113.7mg, yield: 89%, ee% (enantiomeric excess): 82%).
The synthetic route is as follows:
HPLC conditions: OD-H column (n-hexane/isopropanol=90/10, flow rate 1.0 ml/min), retention time: t R =12.8 min (secondary), t R =22.1 min (primary).
Example 7
The synthesis method for asymmetrically synthesizing the 1, 1-disubstituted-tetrahydro-beta-carboline derivative comprises the following steps:
Ligand L7 (12.1 mg,0.03 mmol) and copper chloride (4 mg,0.03 mmol) were weighed into a 40mL reaction flask, evacuated with a vacuum pump for 2h, then nitrogen was added, anhydrous tetrahydrofuran (3 mL) was added, and stirring was performed at room temperature for 4h until complete dissolution. A solution of Compound 1 (96.6 mg,0.3 mmol) in 3mL of tetrahydrofuran was then added to the reaction flask. Cooled to-78 ℃, benzoyl chloride (52 μl,0.45 mmol) and triethylamine (46 μl,0.33 mmol) were added sequentially, and the reaction was maintained at-78 ℃ for 12h. The reaction was quenched with saturated aqueous ammonium chloride at-78 ℃, extracted three times with ethyl acetate, the organic phases were combined, backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was isolated using a flash preparative silica gel column (petroleum ether/ethyl acetate=5:1) to give compound (R) -2 (white solid, 55.0mg, yield: 43%, ee% (enantiomeric excess): 47%).
The synthetic route is as follows:
HPLC conditions: OD-H column (n-hexane/isopropanol=90/10, flow rate 1.0 ml/min), retention time: t R =12.8 min (secondary), t R =22.1 min (primary).
Example 8
The synthesis method for asymmetrically synthesizing the 1, 1-disubstituted-tetrahydro-beta-carboline derivative comprises the following steps:
Ligand L7 (24.2 mg,0.06 mmol) and copper chloride (8 mg,0.06 mmol) were weighed into a 40mL reaction flask, evacuated with a vacuum pump for 2h, then nitrogen was added, anhydrous tetrahydrofuran (3 mL) was added, and stirring was performed at room temperature for 6h until complete dissolution. A solution of Compound 1 (96.6 mg,0.3 mmol) in 3mL of tetrahydrofuran was then added to the reaction flask. Cooled to-78 ℃, benzoyl chloride (104 μl,0.9 mmol) and triethylamine (92 μl,0.66 mmol) were added in sequence, and the reaction was maintained at-78 ℃ for 24h. The reaction was quenched with saturated aqueous ammonium chloride at-78 ℃, extracted three times with ethyl acetate, the organic phases were combined, backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was isolated using a flash preparative silica gel column (petroleum ether/ethyl acetate=5:1) to give compound (R) -2 (white solid, 72.8mg, yield: 57%, ee% (enantiomeric excess): 49%).
The synthetic route is as follows:
HPLC conditions: OD-H column (n-hexane/isopropanol=90/10, flow rate 1.0 ml/min), retention time: t R =12.8 min (secondary), t R =22.1 min (primary).
Example 9
The synthesis method for asymmetrically synthesizing the 1, 1-disubstituted-tetrahydro-beta-carboline derivative comprises the following steps:
Ligand L8 (14.6 mg,0.03 mmol) and copper chloride (4 mg,0.03 mmol) were weighed into a 40mL reaction flask, evacuated with a vacuum pump for 2h, then nitrogen was added, anhydrous tetrahydrofuran (3 mL) was added, and stirring was performed at room temperature for 6h until complete dissolution. A solution of Compound 1 (96.6 mg,0.3 mmol) in 3mL of tetrahydrofuran was then added to the reaction flask. Cooled to-78 ℃, benzoyl chloride (52 μl,0.45 mmol) and triethylamine (46 μl,0.33 mmol) were added in sequence, and the reaction was maintained at-78 ℃ for 24h. The reaction was quenched with saturated aqueous ammonium chloride at-78 ℃, extracted three times with ethyl acetate, the organic phases were combined, backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was isolated using a flash preparative silica gel column (petroleum ether/ethyl acetate=5:1) to give compound (S) -2 (white solid, 29.4mg, yield: 23%, ee% (enantiomeric excess): 5%).
The synthetic route is as follows:
HPLC conditions: OD-H column (n-hexane/isopropanol=90/10, flow rate 1.0 ml/min), retention time: t R =12.8 min (primary), t R =22.1 min (secondary).
Example 10
The synthesis method for asymmetrically synthesizing the 1, 1-disubstituted-tetrahydro-beta-carboline derivative comprises the following steps:
Ligand L8 (146 mg,0.3 mmol) and copper chloride (40 mg,0.3 mmol) were weighed into a 40mL reaction flask, evacuated by a vacuum pump for 2h, then nitrogen was introduced, anhydrous tetrahydrofuran (3 mL) was added, and stirring was performed at room temperature for 6h until complete dissolution. A solution of Compound 1 (96.6 mg,0.3 mmol) in 3mL of tetrahydrofuran was then added to the reaction flask. Cooled to-78 ℃, benzoyl chloride (347 μl,3 mmol) and triethylamine (414 μl,3 mmol) were added in sequence, and the reaction was maintained at-78 ℃ for 24h. The reaction was quenched with saturated aqueous ammonium chloride at-78 ℃, extracted three times with ethyl acetate, the organic phases were combined, backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was isolated using a flash preparative silica gel column (petroleum ether/ethyl acetate=5:1) to give compound (S) -2 (white solid, 37mg, yield 29%, ee% (enantiomeric excess): 10%).
The synthetic route is as follows:
HPLC conditions: OD-H column (n-hexane/isopropanol=90/10, flow rate 1.0 ml/min), retention time: t R =12.8 min (primary), t R =22.1 min (secondary).
The compounds (S) -2 and (R) -2 synthesized in examples 1 to 10 above have a large yield change due to the ligand-copper chloride coordination effect and the steric hindrance. As shown by the analysis of the results, the bisoxazoline ligand derived from cyclopropyl is selected, and the catalyst is easier to participate in coordination due to smaller steric hindrance, so that the reaction can obtain better yield and ee value.
The structures of all the compounds in examples 1 to 10 above were confirmed by nuclear magnetic resonance spectroscopy, and fig. 1 is a hydrogen spectrum of compound 1; FIG. 2 is a carbon spectrum of Compound 1; FIG. 3 is a hydrogen spectrum of compound (S) -2 and compound (R) -2; FIG. 4 is a carbon spectrum of compound (S) -2 and compound (R) -2; the authentication data are as follows:
Compound 1:
1H NMR(500MHz,DMSO-d6)δ10.55(s,1H),7.43(d,J＝7.5Hz,2H),7.31-7.38(m,4H),7.24(t,J＝7.3Hz,1H),7.03(t,J＝7.6Hz,1H),6.94(t,J＝7.4Hz,1H),4.50-4.41(m,2H),4.03(s,2H),3.98-3.82(m,4H),2.96(t,J＝5.6Hz,2H),2.55(t,J＝5.6Hz,2H).
13C NMR(125MHz,DMSO-d6)δ141.4,136.1,136.0,128.2,128.1,126.5,126.4,120.3,117.9,117.3,111.1,109.2,62.9,62.6,52.6,44.6,21.2.
Compound (S) -2 and compound (R) -2 (enantiomers from each other, nuclear magnetic patterns are identical):
1H NMR(500MHz,CDCl3)δ8.62(s,1H),8.09-7.99(m,2H),7.65-7.58(m,1H),7.53-7.45(m,3H),7.42-7.37(m,2H),7.36-7.31(m,3H),7.30-7.27(m,1H),7.18(ddd,J＝8.2,7.1,1.2Hz,1H),7.10(ddd,J＝8.0,7.1,1.1Hz,1H),4.96(d,J＝12.1Hz,1H),4.81(d,J＝12.1Hz,1H),4.27(d,J＝14.0Hz,1H),4.13(d,J＝11.1Hz,1H),4.02(d,J＝11.1Hz,1H),3.74(d,J＝14.0Hz,1H),3.18(brs,1H),3.16-2.97(m,2H),2.82-2.64(m,2H).
13C NMR(125MHz,DMSO-d6)δ165.7,141.2,136.2,134.5,133.3,129.7,129.1,128.7,128.1,127.9,126.5,126.2,120.6,118.1,117.5,111.2,109.6,65.3,63.4,61.4,52.7,44.8,21.2.
The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.
Claims (10)
1. An asymmetric synthesis method of a1, 1-disubstituted-tetrahydro-beta-carboline derivative is characterized by comprising the following steps:
(1) In a reactor, the chiral ligand and the copper chloride are pumped to be dry at room temperature to remove the water of a reaction system, and then an organic solvent is added; adding an organic solvent containing a compound 1 under an inert atmosphere, cooling, and sequentially adding benzoyl chloride and triethylamine to react;
(2) After the reaction is finished, separating and purifying the reaction liquid to obtain the 1, 1-disubstituted-tetrahydro-beta-carboline derivative;
The structural formula of the compound 1 is
Wherein R 1 is one of methoxy, methyl, fluorine, bromine and hydrogen, and R 2 is one of benzyl, 4-bromobenzyl and 4-methoxybenzyl.
2. The method for asymmetric synthesis of 1, 1-disubstituted-tetrahydro- β -carboline derivatives according to claim 1, wherein the organic solvent in step (1) is one of methanol, ethanol, N-propanol, isopropanol, tert-butanol, acetonitrile, ethyl acetate, dichloromethane, dichloroethane, chloroform, tetrahydrofuran, acetone, toluene, N-dimethylformamide, dimethyl sulfoxide, 2-methyltetrahydrofuran, diethyl ether, tert-butyldimethyl ether, and 1, 4-dioxane.
3. The method for asymmetric synthesis of 1, 1-disubstituted-tetrahydro- β -carboline derivatives according to claim 1, wherein the inert atmosphere in step (1) is a nitrogen atmosphere.
4. The method for asymmetric synthesis of 1, 1-disubstituted-tetrahydro- β -carboline derivatives according to claim 1, wherein the chiral ligand of step (1) has the general structural formula:
Wherein R 3 is one of benzyl, phenyl, isopropyl, sec-butyl, tert-butyl, n-butyl, benzocyclopentyl, 2- (methylene) naphthyl and 1- (methylene) naphthyl, R 4 is one of methyl, ethyl, n-butyl, tert-butyl, phenyl and hydrogen atom, and R 5 is one of methyl, cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl.
5. The method for asymmetric synthesis of 1, 1-disubstituted-tetrahydro- β -carboline derivatives according to claim 1, wherein the molar ratio of compound 1 to chiral ligand in step (1) is 1:0.1 to 1:1.
6. The method for asymmetric synthesis of 1, 1-disubstituted-tetrahydro- β -carboline derivatives according to claim 1, wherein the molar ratio of compound 1 to copper chloride in step (1) is 1:0.1 to 1:1.
7. The method for asymmetric synthesis of 1, 1-disubstituted-tetrahydro- β -carboline derivatives according to claim 1, wherein the temperature of step (1) is reduced to-78 ℃ and the reaction time is 12-120 h at the temperature.
8. The method for asymmetric synthesis of 1, 1-disubstituted-tetrahydro- β -carboline derivatives according to claim 1, wherein the molar ratio of compound 1 to benzoyl chloride in step (1) is 1:1.1 to 1:10.
9. The method for asymmetric synthesis of 1, 1-disubstituted-tetrahydro- β -carboline derivatives according to claim 1, wherein the molar ratio of compound 1 to triethylamine in step (1) is 1:1.1 to 1:10.
10. The asymmetric synthesis method of a1, 1-disubstituted-tetrahydro- β -carboline derivative according to any one of claims 1 to 9, wherein the specific steps of separation and purification in step (2) are: the saturated ammonium chloride aqueous solution is quenched, extracted by ethyl acetate, backwashed by saturated sodium chloride solution, dried by anhydrous sodium sulfate, filtered, and the organic phase is concentrated, and separated and purified by column chromatography.
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