CN113121421A - Synthesis method of chiral beta-aryl substituted carboxylic acid derivative - Google Patents
Synthesis method of chiral beta-aryl substituted carboxylic acid derivative Download PDFInfo
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- CN113121421A CN113121421A CN202110280387.0A CN202110280387A CN113121421A CN 113121421 A CN113121421 A CN 113121421A CN 202110280387 A CN202110280387 A CN 202110280387A CN 113121421 A CN113121421 A CN 113121421A
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- CN
- China
- Prior art keywords
- aryl
- carboxylic acid
- acid derivatives
- substituted carboxylic
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 150000001732 carboxylic acid derivatives Chemical class 0.000 title claims abstract description 53
- 238000001308 synthesis method Methods 0.000 title description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 74
- 238000006243 chemical reaction Methods 0.000 claims abstract description 67
- 238000000034 method Methods 0.000 claims abstract description 52
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 42
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 37
- 239000003054 catalyst Substances 0.000 claims abstract description 36
- 239000003446 ligand Substances 0.000 claims abstract description 14
- -1 aliphatic amide compound Chemical class 0.000 claims abstract description 13
- 239000000126 substance Substances 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 5
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 90
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 60
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 60
- 229910052731 fluorine Inorganic materials 0.000 claims description 33
- DVWQNBIUTWDZMW-UHFFFAOYSA-N 1-naphthalen-1-ylnaphthalen-2-ol Chemical group C1=CC=C2C(C3=C4C=CC=CC4=CC=C3O)=CC=CC2=C1 DVWQNBIUTWDZMW-UHFFFAOYSA-N 0.000 claims description 31
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 30
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- 125000003118 aryl group Chemical group 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 16
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- 150000001503 aryl iodides Chemical class 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 239000011591 potassium Substances 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
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- 125000004171 alkoxy aryl group Chemical group 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000005036 alkoxyphenyl group Chemical group 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000005059 halophenyl group Chemical group 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 125000006501 nitrophenyl group Chemical group 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 229910052710 silicon Inorganic materials 0.000 claims description 2
- 239000010703 silicon Substances 0.000 claims description 2
- 125000001424 substituent group Chemical group 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
- 238000006254 arylation reaction Methods 0.000 abstract description 5
- 238000006555 catalytic reaction Methods 0.000 abstract 1
- 238000004440 column chromatography Methods 0.000 abstract 1
- 239000011630 iodine Substances 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- 239000000376 reactant Substances 0.000 description 56
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 28
- 238000004587 chromatography analysis Methods 0.000 description 28
- 239000011737 fluorine Substances 0.000 description 28
- 239000000741 silica gel Substances 0.000 description 28
- 229910002027 silica gel Inorganic materials 0.000 description 28
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 229940125904 compound 1 Drugs 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 6
- 229940126086 compound 21 Drugs 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 238000010499 C–H functionalization reaction Methods 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 3
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 3
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 3
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-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
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 2
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 2
- OJRUSAPKCPIVBY-KQYNXXCUSA-N C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N Chemical compound C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N OJRUSAPKCPIVBY-KQYNXXCUSA-N 0.000 description 2
- RRSNDVCODIMOFX-MPKOGUQCSA-N Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O Chemical compound Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O RRSNDVCODIMOFX-MPKOGUQCSA-N 0.000 description 2
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 2
- 238000007036 catalytic synthesis reaction Methods 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940125961 compound 24 Drugs 0.000 description 2
- 229940125846 compound 25 Drugs 0.000 description 2
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- 229940125898 compound 5 Drugs 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
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- PPTXVXKCQZKFBN-UHFFFAOYSA-N (S)-(-)-1,1'-Bi-2-naphthol Chemical class C1=CC=C2C(C3=C4C=CC=CC4=CC=C3O)=C(O)C=CC2=C1 PPTXVXKCQZKFBN-UHFFFAOYSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
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- 230000000707 stereoselective effect Effects 0.000 description 1
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- 229910052723 transition metal Inorganic materials 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/40—Acylated substituent nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
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Abstract
The invention discloses a method for synthesizing chiral beta-aryl substituted carboxylic acid derivatives. The method comprises the steps of reacting an aliphatic amide compound and aryl iodine in a chiral ligand, an alkaline substance and a solvent under the catalysis of a palladium catalyst, and purifying and separating by column chromatography to obtain a chiral beta-aryl substituted carboxylic acid derivative; the method has the advantages of mild reaction conditions, cheap used raw materials, simple process, convenient operation and high yield of arylation products with high stereoselectivity.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a synthesis method of chiral beta-aryl substituted carboxylic acid derivatives.
Background
The conversion of carbon-hydrogen (C-H) bonds and the construction of carbon-carbon (C-C) bonds constitute an important part of the research in organic chemistry. It is considered to have low chemical activity due to saturation and stability of the carbon-hydrogen bond. Asymmetric catalytic synthesis is a hot spot in the current research field of organic synthetic chemistry. The design and development of excellent chiral ligands and catalyst systems are the key points of asymmetric catalytic synthesis; because of the few ligands suitable for asymmetric carbon-hydrogen bond activation, the development of the asymmetric carbon-hydrogen bond activation reaction is relatively slow. For inert methylene groups, stereoselective identification through insertion of metal into carbon-hydrogen bonds remains a significant challenge due to the similarity of the hydrogen atom environment.
The methods for transition metal catalyzed asymmetric C-H/C-C activation in the related art mainly comprise: pd (II) catalyzed asymmetric carbon-hydrogen bond activation reaction by using N-protected amino acid (MPAA) as a chiral ligand; chiral oxazoline is introduced as a guiding group, so that the asymmetric arylation reaction of the beta-benzyl is realized; chiral phosphamide is used as ligand to perform arylation reaction for removing symmetry of methylene at benzyl position. The related art functionalization methods related to asymmetric carbon-hydrogen bonds are relatively complex, and the ligands used in the methods are relatively expensive, and are relatively complex and unavailable.
Therefore, a new synthesis method of chiral β -aryl substituted carboxylic acid derivatives needs to be developed; the method can realize the asymmetric carbon-hydrogen bond activation of inert methylene group with regioselectivity and stereoselectivity controlled by ligand.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: provides a method for synthesizing chiral beta-aryl substituted carboxylic acid derivatives, which has good selectivity and higher product yield.
In order to solve the technical problems, the technical scheme provided by the invention is as follows: a method for synthesizing chiral beta-aryl substituted carboxylic acid derivatives comprises the following steps: reacting an amide compound with an aryl iodide compound in a palladium catalyst, a chiral ligand, an alkaline substance and a solvent to prepare a beta-arylated carboxylic acid derivative shown as the following formula III;
wherein the amide compound is selected from a compound shown as a formula I;
the aryl iodide is selected from one of compounds shown as a formula II-1, a formula II-2 or a formula II-3;
r is selected from H, alkyl, alkoxy aryl, halogenated aryl or alkoxy silicon;
x is selected from nitro, alkyl, alkoxy, aryl, halogen atom, trifluoromethyl, trifluoromethoxy or ester group.
According to some embodiments of the invention, said R and/or X are independently selected from alkyl; preferably, the alkyl group is C1～20An alkyl group; preferably, the alkyl group is C1～10An alkyl group; preferably, the alkyl group is at least one of methyl, ethyl, propyl, butyl, and tert-butyl.
According to some embodiments of the invention, the halogen atom is at least one of a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom; preferably, the halogen atom is a chlorine atom.
According to some embodiments of the invention, said R and/or X are independently selected from aryl; said aryl group is C20The following aryl groups; preferably, said aryl is C10The following aryl groups; preferably, the aryl group is an alkylaryl, alkoxyphenyl, nitrophenyl, halophenyl or heteroaryl group.
According to some embodiments of the invention, the alkylaryl group is a mono-or di-substituted alkylaryl group; preferably, the alkyl group in the alkylaryl group is C1～8An alkyl group; preferably, said C1～8Alkyl groups include, but are not limited to, methyl and t-butyl.
According to some embodiments of the invention, the halogenated aryl is mono-or di-substituted phenyl; preferably, the halo is F, Cl or Br; preferably, the disubstituted substituents are the same or different;
according to some embodiments of the invention, the heteroaryl refers to C10A heterocycle containing at least one of N and O; preferably, the heterocycle is C5The following nitrogen-containing heterocyclic ring; preferably, the nitrogen-containing heterocycle is pyridyl.
According to some embodiments of the invention, the β -arylated carboxylic acid derivative comprises compound 1 to compound 28 of the formula:
according to some embodiments of the invention, the palladium catalyst comprises palladium hexafluoroacetylacetonate.
According to some embodiments of the invention, the alkaline substance is a potassium-containing inorganic alkaline substance; preferably, the potassium-containing inorganic alkaline substance comprises potassium carbonate.
According to some embodiments of the invention, the chiral ligand comprises binaphthol substituted with a fluorine atom at the 3, 3' position.
The BINOL derivative which is easy to obtain and adjustable is selected as a chiral ligand; the high stereoselectivity of the reaction is realized through the chiral control of the binaphthol substituted by fluorine atoms at 3, 3' positions.
According to some embodiments of the invention, the solvent is an organic solvent; preferably, the organic solvent includes at least one of t-butanol and toluene.
According to some embodiments of the invention, the temperature of the reaction is between 100 ℃ and 110 ℃; preferably, the reaction time is 12h to 14 h.
According to some embodiments of the invention, the molar ratio of the aryl iodide compound, the palladium catalyst, the chiral ligand and the basic substance is 0.9 to 1.1: 0.09-0.11: 0.18 to 0.22: 2.4 to 2.6.
The method for synthesizing the chiral beta-aryl substituted carboxylic acid derivative has at least the following beneficial effects: the aryl iodide with low reaction activity and cost benefit is selected as the arylation reagent, so that the reaction cost is reduced; the products (carboxylic acid derivatives) of the invention are well tolerated and have a high enantioselectivity; this synthetic route produces products with high ee values.
Drawings
FIG. 1 is an HPLC chromatogram of compound 1 and racemate (mass ratio 1:1) obtained in the first embodiment of the present invention;
FIG. 2 is an HPLC chromatogram of the product obtained in the first example of the present invention;
FIG. 3 is an HPLC chromatogram of compound 21 and racemate (mass ratio 1:1) obtained in the first embodiment of the present invention;
FIG. 4 is an HPLC chromatogram of a product obtained in twenty-one example of the invention.
Detailed Description
The concept and technical effects of the present invention will be clearly and completely described below in conjunction with the embodiments to fully understand the objects, features and effects of the present invention. It is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments, and those skilled in the art can obtain other embodiments without inventive effort based on the embodiments of the present invention, and all embodiments are within the protection scope of the present invention.
The first embodiment of the invention is as follows: a method for synthesizing chiral beta-aryl substituted carboxylic acid derivatives comprises the following steps:
adding 0.1mmol of reactant 1, 0.2mmol of reactant 2, 0.01mmol of palladium hexafluoroacetylacetonate catalyst, 0.02mmol of 3, 3' -fluorine substituted binaphthol, 0.25mmol of potassium carbonate, 0.8mL of tert-butanol and 0.2mL of toluene in a reaction vessel, and reacting at 105 ℃ for 12 hours to terminate the reaction; compound 1 was obtained by thin layer silica gel plate chromatography, wherein the yield of Compound 1 was 82% and ee value was 92%.
The structural characterization data is as follows:
1H NMR(400MHz,CDCl3)δ8.47(ddd,J＝4.8,2.0,1.2Hz,1H),7.65(td,J＝8.0,1.6Hz,1H),7.46(s,1H),7.28(dt,J＝8.0,1.2Hz,1H),7.18–7.14(m,3H),7.10(s,1H),7.09(d,J＝8.0Hz,1H),3.34–3.24(m,1H),2.52(dd,J＝14.0,7.2Hz,1H),2.43(dd,J＝14.0,8.0Hz,1H),2.30(s,3H),1.68(s,3H),1.64(s,3H),1.30(d,J＝7.2Hz,3H).
13C NMR(101MHz,CDCl3)δ171.1,164.6,147.7,143.3,137.1,135.8,129.2,126.9,121.8,119.5,56.6,46.9,36.8,27.6,27.5,21.8,21.1.
HRMS(ESI)m/z:[M+H]+Calcd for C19H24N2OH,(M+H)+:297.1962,found:297.1961.；
the chromatographic test conditions of the compound prepared in the first embodiment of the invention and the racemate thereof are as follows:
the chromatographic column is as follows: daicel Chiralpak;
the mobile phase is as follows: hexane to isopropanol (70: 30 by volume);
the flow rate is 1.0 mL/min;
the detection wavelength is as follows: 254 nm.
The chromatographic test results of the compound 1 and the racemate prepared by the method (mass ratio is 1:1) are shown in a figure 1 and a table 1.
TABLE 1 chromatographic test results of Compound 1 and its racemate (mass ratio 1:1) obtained in example one of the present invention
The chromatographic detection results of the product of the first example of the invention are shown in fig. 2 and table 2.
TABLE 2 chromatographic test results of the product of the first example of the present invention
The second embodiment of the invention is as follows: a method for synthesizing chiral beta-aryl substituted carboxylic acid derivatives comprises the following steps:
adding 0.1mmol of reactant 1, 0.2mmol of reactant 3, 0.01mmol of palladium hexafluoroacetylacetonate catalyst, 0.02mmol of 3, 3' -fluorine substituted binaphthol, 0.25mmol of potassium carbonate, 0.8mL of tert-butanol and 0.2mL of toluene in a reaction vessel, and reacting at 105 ℃ for 12 hours to terminate the reaction; compound 2 was obtained by thin layer silica gel plate chromatography in which the yield of Compound 2 was 77% and ee was 92%.
The third embodiment of the invention is as follows: a method for synthesizing chiral beta-aryl substituted carboxylic acid derivatives comprises the following steps:
adding 0.1mmol of reactant 1, 0.2mmol of reactant 4, 0.01mmol of palladium hexafluoroacetylacetonate catalyst, 0.02mmol of 3, 3' -fluorine substituted binaphthol, 0.25mmol of potassium carbonate, 0.8mL of tert-butanol and 0.2mL of toluene in a reaction vessel, and reacting at 105 ℃ for 12 hours to terminate the reaction; compound 3 was obtained by thin layer silica gel plate chromatography in which the yield of compound 3 was 70% and ee value was 94%.
The fourth embodiment of the invention is as follows: a method for synthesizing chiral beta-aryl substituted carboxylic acid derivatives comprises the following steps:
adding 0.1mmol of reactant 1, 0.2mmol of reactant 5, 0.01mmol of palladium hexafluoroacetylacetonate catalyst, 0.02mmol of 3, 3' -fluorine substituted binaphthol, 0.25mmol of potassium carbonate, 0.8mL of tert-butanol and 0.2mL of toluene in a reaction vessel, and reacting at 105 ℃ for 12 hours to terminate the reaction; compound 4 was obtained by thin layer silica gel plate chromatography in 55% yield and 92% ee.
The fifth embodiment of the invention is as follows: a method for synthesizing chiral beta-aryl substituted carboxylic acid derivatives comprises the following steps:
adding 0.1mmol of reactant 1, 0.2mmol of reactant 6, 0.01mmol of palladium hexafluoroacetylacetonate catalyst, 0.02mmol of 3, 3' -fluorine substituted binaphthol, 0.25mmol of potassium carbonate, 0.8mL of tert-butanol and 0.2mL of toluene in a reaction vessel, and reacting at 105 ℃ for 12 hours to terminate the reaction; compound 5 was obtained by thin layer silica gel plate chromatography, wherein the yield of Compound 5 was 60% and ee value was 91%.
The sixth embodiment of the invention is as follows: a method for synthesizing chiral beta-aryl substituted carboxylic acid derivatives comprises the following steps:
adding 0.1mmol of reactant 1, 0.2mmol of reactant 7, 0.01mmol of palladium hexafluoroacetylacetonate catalyst, 0.02mmol of 3, 3' -fluorine substituted binaphthol, 0.25mmol of potassium carbonate, 0.8mL of tert-butanol and 0.2mL of toluene in a reaction vessel, and reacting at 105 ℃ for 12 hours to terminate the reaction; compound 6 was obtained by thin layer silica gel plate chromatography in which the yield of Compound 6 was 70% and ee was 91%.
The seventh embodiment of the invention is: a method for synthesizing chiral beta-aryl substituted carboxylic acid derivatives comprises the following steps:
adding 0.1mmol of reactant 1, 0.2mmol of reactant 8, 0.01mmol of palladium hexafluoroacetylacetonate catalyst, 0.02mmol of 3, 3' -fluorine substituted binaphthol, 0.25mmol of potassium carbonate, 0.8mL of tert-butanol and 0.2mL of toluene in a reaction vessel, and reacting at 105 ℃ for 12 hours to terminate the reaction; compound 7 was obtained by thin layer silica gel plate chromatography, wherein the yield of Compound 7 was 68% and ee value was 91%.
The eighth embodiment of the present invention is: a method for synthesizing chiral beta-aryl substituted carboxylic acid derivatives comprises the following steps:
adding 0.1mmol of reactant 1, 0.2mmol of reactant 9, 0.01mmol of palladium hexafluoroacetylacetonate catalyst, 0.02mmol of 3, 3' -fluorine substituted binaphthol, 0.25mmol of potassium carbonate, 0.8mL of tert-butanol and 0.2mL of toluene in a reaction vessel, and reacting at 105 ℃ for 12 hours to terminate the reaction; compound 8 was obtained by thin layer silica gel plate chromatography in which the yield of compound 8 was 57% and ee value was 90%.
The ninth embodiment of the invention is: a method for synthesizing chiral beta-aryl substituted carboxylic acid derivatives comprises the following steps:
adding 0.1mmol of reactant 1, 0.2mmol of reactant 10, 0.01mmol of palladium hexafluoroacetylacetonate catalyst, 0.02mmol of 3, 3' -fluorine substituted binaphthol, 0.25mmol of potassium carbonate, 0.8mL of tert-butanol and 0.2mL of toluene in a reaction vessel, and reacting at 105 ℃ for 12 hours to terminate the reaction; compound 9 was obtained by thin layer silica gel plate chromatography, wherein the yield of compound 9 was 45% and ee value was 92%.
The tenth embodiment of the present invention is: a method for synthesizing chiral beta-aryl substituted carboxylic acid derivatives comprises the following steps:
adding 0.1mmol of reactant 1, 0.2mmol of reactant 11, 0.01mmol of palladium hexafluoroacetylacetonate catalyst, 0.02mmol of 3, 3' -fluorine substituted binaphthol, 0.25mmol of potassium carbonate, 0.8mL of tert-butanol and 0.2mL of toluene in a reaction vessel, and reacting at 105 ℃ for 12 hours to terminate the reaction; compound 10 was obtained by thin layer silica gel plate chromatography, wherein the yield of Compound 10 was 83% and ee value was 91%.
The eleventh embodiment of the present invention is: a method for synthesizing chiral beta-aryl substituted carboxylic acid derivatives comprises the following steps:
adding 0.1mmol of reactant 1, 0.2mmol of reactant 12, 0.01mmol of palladium hexafluoroacetylacetonate catalyst, 0.02mmol of 3, 3' -fluorine substituted binaphthol, 0.25mmol of potassium carbonate, 0.8mL of tert-butanol and 0.2mL of toluene in a reaction vessel, and reacting at 105 ℃ for 12 hours to terminate the reaction; compound 1 was obtained by thin layer silica gel plate chromatography in 82% yield and 91% ee of compound 11.
The twelfth embodiment of the present invention is: a method for synthesizing chiral beta-aryl substituted carboxylic acid derivatives comprises the following steps:
adding 0.1mmol of reactant 1, 0.2mmol of reactant 13, 0.01mmol of palladium hexafluoroacetylacetonate catalyst, 0.02mmol of 3, 3' -fluorine substituted binaphthol, 0.25mmol of potassium carbonate, 0.8mL of tert-butanol and 0.2mL of toluene in a reaction vessel, and reacting at 105 ℃ for 12 hours to terminate the reaction; compound 12 was obtained by thin layer silica gel plate chromatography in which the yield of compound 12 was 54% and ee was 93%.
The thirteenth embodiment of the present invention is: a method for synthesizing chiral beta-aryl substituted carboxylic acid derivatives comprises the following steps:
adding 0.1mmol of reactant 1, 0.2mmol of reactant 14, 0.01mmol of palladium hexafluoroacetylacetonate catalyst, 0.02mmol of 3, 3' -fluorine substituted binaphthol, 0.25mmol of potassium carbonate, 0.8mL of tert-butanol and 0.2mL of toluene in a reaction vessel, and reacting at 105 ℃ for 12 hours to terminate the reaction; compound 13 was obtained by thin layer silica gel plate chromatography, wherein the yield of compound 13 was 45% and ee value was 96%.
The fourteenth embodiment of the present invention is: a method for synthesizing chiral beta-aryl substituted carboxylic acid derivatives comprises the following steps:
adding 0.1mmol of reactant 1, 0.2mmol of reactant 15, 0.01mmol of palladium hexafluoroacetylacetonate catalyst, 0.02mmol of 3, 3' -fluorine substituted binaphthol, 0.25mmol of potassium carbonate, 0.8mL of tert-butanol and 0.2mL of toluene in a reaction vessel, and reacting at 105 ℃ for 12 hours to terminate the reaction; compound 14 was obtained by thin layer silica gel plate chromatography in 73% yield and 92% ee.
Fifteenth embodiment of the present invention is: a method for synthesizing chiral beta-aryl substituted carboxylic acid derivatives comprises the following steps:
adding 0.1mmol of reactant 1, 0.2mmol of reactant 16, 0.01mmol of palladium hexafluoroacetylacetonate catalyst, 0.02mmol of 3, 3' -fluorine substituted binaphthol, 0.25mmol of potassium carbonate, 0.8mL of tert-butanol and 0.2mL of toluene in a reaction vessel, and reacting at 105 ℃ for 12 hours to terminate the reaction; compound 15 was obtained by thin layer silica gel plate chromatography in which the yield of compound 15 was 34% and ee was 92%.
The sixteenth embodiment of the present invention is: a method for synthesizing chiral beta-aryl substituted carboxylic acid derivatives comprises the following steps:
adding 0.1mmol of reactant 1, 0.2mmol of reactant 2, 0.01mmol of palladium hexafluoroacetylacetonate catalyst, 0.02mmol of 3, 3' -fluorine substituted binaphthol, 0.25mmol of potassium carbonate, 0.8mL of tert-butanol and 0.2mL of toluene in a reaction vessel, and reacting at 105 ℃ for 12 hours to terminate the reaction; compound 1 was obtained by thin layer silica gel plate chromatography in which the yield of compound 16 was 57% and ee was 92%.
Seventeenth embodiment of the present invention is: a method for synthesizing chiral beta-aryl substituted carboxylic acid derivatives comprises the following steps:
adding 0.1mmol of a reactant 18, 0.2mmol of a reactant 3, 0.01mmol of a palladium hexafluoroacetylacetonate catalyst, 0.02mmol of 3, 3' -fluorine atom-substituted binaphthol, 0.25mmol of potassium carbonate, 0.8mL of t-butanol and 0.2mL of toluene in a reaction vessel, and reacting at 105 ℃ for 12 hours to terminate the reaction; compound 17 was obtained by thin layer silica gel plate chromatography in 55% yield and 94% ee.
Eighteen embodiments of the present invention are: a method for synthesizing chiral beta-aryl substituted carboxylic acid derivatives comprises the following steps:
adding 0.1mmol of reactant 19, 0.2mmol of reactant 3, 0.01mmol of palladium hexafluoroacetylacetonate catalyst, 0.02mmol of 3, 3' -fluorine substituted binaphthol, 0.25mmol of potassium carbonate, 0.8mL of tert-butanol and 0.2mL of toluene in a reaction vessel, and reacting at 105 ℃ for 12 hours to terminate the reaction; compound 18 was obtained by thin layer silica gel plate chromatography in 65% yield and 94% ee.
The nineteenth embodiment of the present invention is: a method for synthesizing chiral beta-aryl substituted carboxylic acid derivatives comprises the following steps:
adding 0.1mmol of reactant 20, 0.2mmol of reactant 3, 0.01mmol of palladium hexafluoroacetylacetonate catalyst, 0.02mmol of 3, 3' -fluorine substituted binaphthol, 0.25mmol of potassium carbonate, 0.8mL of tert-butanol and 0.2mL of toluene in a reaction vessel, and reacting at 105 ℃ for 12 hours to terminate the reaction; compound 19 was obtained by thin layer silica gel plate chromatography, wherein the yield of compound 19 was 70% and ee value was 92%.
The twenty embodiment of the present invention is: a method for synthesizing chiral beta-aryl substituted carboxylic acid derivatives comprises the following steps:
adding 0.1mmol of reactant 21, 0.2mmol of reactant 3, 0.01mmol of palladium hexafluoroacetylacetonate catalyst, 0.02mmol of 3, 3' -fluorine substituted binaphthol, 0.25mmol of potassium carbonate, 0.8mL of tert-butanol and 0.2mL of toluene in a reaction vessel, and reacting at 105 ℃ for 12 hours to terminate the reaction; compound 20 was obtained by thin layer silica gel plate chromatography in 52% yield and 62% ee.
The twenty-first embodiment of the present invention is: a method for synthesizing chiral beta-aryl substituted carboxylic acid derivatives comprises the following steps:
adding 0.1mmol of reactant 22, 0.2mmol of reactant 3, 0.01mmol of palladium hexafluoroacetylacetonate catalyst, 0.02mmol of 3, 3' -fluorine substituted binaphthol, 0.25mmol of potassium carbonate, 0.8mL of tert-butanol and 0.2mL of toluene in a reaction vessel, and reacting at 105 ℃ for 12 hours to terminate the reaction; compound 21 was obtained by thin layer silica gel plate chromatography in 55% yield of compound 21 and 94% ee.
The structural characterization data for compound 21 is as follows:
1H NMR(400MHz,CDCl3)δ8.45(ddd,J＝4.8,2.0,1.2Hz,1H),7.65(td,J＝7.6,2.0Hz,1H),7.49(s,1H),7.23–7.14(m,4H),7.10(dt,J＝8.4,2.4Hz,2H),7.00(d,J＝7.6Hz,2H),6.91(dd,J＝8.0,1.6Hz,2H),3.48–3.39(m,1H),2.93(dd,J＝13.6,6.8Hz,1H),2.84(dd,J＝13.6,8.0Hz,1H),2.61(dd,J＝14.0,6.0Hz,1H),2.46(dd,J＝14.0,9.2Hz,1H),2.27(s,3H),1.62(s,3H),1.55(s,3H).
13C NMR(101MHz,CDCl3)δ170.4,164.3,147.5,142.4,137.3,136.4,135.7,132.0,129.3,129.2,129.0,128.4,121.9,119.5,56.5,44.1,43.9,42.3,27.6,27.3,21.1.
HRMS(ESI)m/z:[M+H]+Calcd for C25H27ClN2OH,(M+H)+:407.1885,found:407.1885.
the chromatographic test conditions of the compound prepared in the twenty-first embodiment of the invention and the racemate thereof are as follows:
the chromatographic column is as follows: daicel Chiralpak AD-H;
the mobile phase is as follows: hexane to isopropanol (90: 10 by volume);
the flow rate is 1.0 mL/min;
the detection wavelength is as follows: 254 nm.
The results of the chromatographic test of the compound 21 and the racemate prepared by the method (mass ratio of 1:1) are shown in FIG. 3 and Table 3.
TABLE 3 chromatographic test results of Compound 21 and its racemate (mass ratio 1:1) prepared in twenty-one of the examples of the invention
The chromatographic detection results of the products in twenty one of the examples of the invention are shown in fig. 4 and table 4.
Table 4 chromatographic test results of the products of twenty-one example of the invention
The twenty-second embodiment of the present invention is: a method for synthesizing chiral beta-aryl substituted carboxylic acid derivatives comprises the following steps:
adding 0.1mmol of reactant 23, 0.2mmol of reactant 3, 0.01mmol of palladium hexafluoroacetylacetonate catalyst, 0.02mmol of 3, 3' -fluorine substituted binaphthol, 0.25mmol of potassium carbonate, 0.8mL of tert-butanol and 0.2mL of toluene in a reaction vessel, and reacting at 105 ℃ for 12 hours to terminate the reaction; compound 22 was obtained by thin layer silica gel plate chromatography in 49% yield and 94% ee.
Twenty three embodiments of the present invention are: a method for synthesizing chiral beta-aryl substituted carboxylic acid derivatives comprises the following steps:
adding 0.1mmol of reactant 24, 0.2mmol of reactant 7, 0.01mmol of palladium hexafluoroacetylacetonate catalyst, 0.02mmol of 3, 3' -fluorine substituted binaphthol, 0.25mmol of potassium carbonate, 0.8mL of tert-butanol and 0.2mL of toluene in a reaction vessel, and reacting at 105 ℃ for 12 hours to terminate the reaction; compound 23 was obtained by thin layer silica gel plate chromatography in 84% yield and 92% ee.
Twenty-four embodiments of the present invention are: a method for synthesizing chiral beta-aryl substituted carboxylic acid derivatives comprises the following steps:
adding 0.1mmol of reactant 25, 0.2mmol of reactant 7, 0.01mmol of palladium hexafluoroacetylacetonate catalyst, 0.02mmol of 3, 3' -fluorine substituted binaphthol, 0.25mmol of potassium carbonate, 0.8mL of tert-butanol and 0.2mL of toluene in a reaction vessel, and reacting at 105 ℃ for 12 hours to terminate the reaction; compound 24 was obtained by thin layer silica gel plate chromatography in which the yield of compound 24 was 63% and ee was 92%.
Twenty five embodiments of the present invention are: a method for synthesizing chiral beta-aryl substituted carboxylic acid derivatives comprises the following steps:
adding 0.1mmol of a reactant 26, 0.2mmol of a reactant 7, 0.01mmol of a palladium hexafluoroacetylacetonate catalyst, 0.02mmol of 3, 3' -fluorine substituted binaphthol, 0.25mmol of potassium carbonate, 0.8mL of t-butanol and 0.2mL of toluene in a reaction vessel, and reacting at 105 ℃ for 12 hours to terminate the reaction; compound 25 was obtained by thin layer silica gel plate chromatography in which the yield of compound 25 was 54% and ee was 92%.
Twenty-six embodiments of the present invention are: a method for synthesizing chiral beta-aryl substituted carboxylic acid derivatives comprises the following steps:
adding 0.1mmol of reactant 27, 0.2mmol of reactant 7, 0.01mmol of palladium hexafluoroacetylacetonate catalyst, 0.02mmol of 3, 3' -fluorine substituted binaphthol, 0.25mmol of potassium carbonate, 0.8mL of tert-butanol and 0.2mL of toluene in a reaction vessel, and reacting at 105 ℃ for 12 hours to terminate the reaction; compound 26 was obtained by thin layer silica gel plate chromatography in 47% yield and 92% ee.
Twenty-seventh of the embodiments of the present invention is: a method for synthesizing chiral beta-aryl substituted carboxylic acid derivatives comprises the following steps:
adding 0.1mmol of reactant 28, 0.2mmol of reactant 7, 0.01mmol of palladium hexafluoroacetylacetonate catalyst, 0.02mmol of 3, 3' -fluorine substituted binaphthol, 0.25mmol of potassium carbonate, 0.8mL of tert-butanol and 0.2mL of toluene in a reaction vessel, and reacting at 105 ℃ for 12 hours to terminate the reaction; compound 27 was obtained by thin layer silica gel plate chromatography in which the yield of compound 27 was 70% and ee value was 90%.
Twenty-eight embodiments of the present invention are: a method for synthesizing chiral beta-aryl substituted carboxylic acid derivatives comprises the following steps:
adding 0.1mmol of reactant 29, 0.2mmol of reactant 7, 0.01mmol of palladium hexafluoroacetylacetonate catalyst, 0.02mmol of 3, 3' -fluorine substituted binaphthol, 0.25mmol of potassium carbonate, 0.8mL of tert-butanol and 0.2mL of toluene in a reaction vessel, and reacting at 105 ℃ for 12 hours to terminate the reaction; compound 28 was obtained by thin layer silica gel plate chromatography in 93% yield and 90% ee.
In conclusion, the synthesis method provided by the invention adopts the aryl iodide with low reaction activity and cost benefit as the arylation reagent, so that the reaction cost is reduced; the products (carboxylic acid derivatives) of the invention are well tolerated and have a high enantioselectivity; this synthetic route enables the preparation of products with high ee values.
While the embodiments of the present invention have been described in detail with reference to the description and the drawings, the present invention is not limited to the embodiments, and various changes can be made without departing from the gist of the present invention within the knowledge of those skilled in the art. Furthermore, the embodiments of the present invention and the features of the embodiments may be combined with each other without conflict.
Claims (10)
1. A method for synthesizing chiral beta-aryl substituted carboxylic acid derivatives is characterized in that: the method comprises the following steps: reacting an amide compound with an aryl iodide compound in a palladium catalyst, a chiral ligand, an alkaline substance and a solvent to prepare a beta-arylated carboxylic acid derivative shown as the following formula III;
wherein the amide compound is selected from a compound shown as a formula I;
the aryl iodide is selected from one of compounds shown as a formula II-1, a formula II-2 or a formula II-3;
r is selected from H, alkyl, alkoxy aryl, halogenated aryl or alkoxy silicon;
x is selected from nitro, alkyl, alkoxy, aryl, halogen atom, trifluoromethyl, trifluoromethoxy or ester group.
2. The method for synthesizing chiral β -aryl substituted carboxylic acid derivatives according to claim 1, wherein: r and/or X are independently selected from alkyl; preferably, the alkyl group is C1～20An alkyl group; preferably, the alkyl group is C1～10An alkyl group; preferably, the alkyl group is at least one of methyl, ethyl, propyl, butyl and tert-butyl;
preferably, the halogen atom is at least one of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; preferably, the halogen atom is a bromine atom.
3. The method for synthesizing chiral β -aryl substituted carboxylic acid derivatives according to claim 1, wherein: r and/or X are independently selected from aryl; preferably, said aryl is C20The following aryl groups; preferably, said aryl is C10The following aryl groups; preferably, the aryl group is an alkylaryl, alkoxyphenyl, nitrophenyl, halophenyl or heteroaryl group;
preferably, the alkylaryl group is a mono-or di-substituted alkylaryl group; preferably, the alkyl group in the alkylaryl group is C1～8An alkyl group; preferably, said C1～8Alkyl groups include, but are not limited to, methyl and t-butyl;
preferably, the halogenated aryl group is a mono-or di-substituted phenyl group; preferably, the halo is F, Cl or Br; preferably, the disubstituted substituents are the same or different;
more preferably, said heteroaryl means C10A heterocycle containing at least one of N and O; further preferably, the heterocycle is C5The following nitrogen-containing heterocyclic ring; still more preferably, the nitrogen-containing heterocycle is pyridyl.
4. The method for synthesizing chiral β -aryl substituted carboxylic acid derivatives according to claim 1, wherein: the β -arylated carboxylic acid derivatives include compounds 1 to 28 represented by the following formulae:
5. the method for synthesizing chiral β -aryl substituted carboxylic acid derivatives according to claim 1, wherein: the palladium catalyst comprises palladium hexafluoroacetylacetonate.
6. The method for synthesizing chiral β -aryl substituted carboxylic acid derivatives according to claim 1, wherein: the alkaline substance is a potassium-containing alkaline substance; preferably, the potassium-containing basic substance comprises potassium carbonate.
7. The method for synthesizing chiral β -aryl substituted carboxylic acid derivatives according to claim 1, wherein: the chiral ligand comprises binaphthol substituted by fluorine atoms at 3, 3' positions.
8. The method for synthesizing chiral β -aryl substituted carboxylic acid derivatives according to claim 1, wherein: the solvent is an organic solvent; preferably, the organic solvent includes at least one of t-butanol and toluene.
9. The method for synthesizing chiral β -aryl substituted carboxylic acid derivatives according to claim 1, wherein: the reaction temperature is 100-110 ℃; preferably, the reaction time is 12h to 14 h.
10. The method for synthesizing chiral β -aryl substituted carboxylic acid derivatives according to claim 1, wherein: the molar ratio of the aryl iodide compound to the palladium catalyst to the chiral ligand to the alkaline substance is 0.9-1.1: 0.09-0.11: 0.18 to 0.22: 2.4 to 2.6.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113731506A (en) * | 2021-09-28 | 2021-12-03 | 常州大学 | Method for assisting palladium-catalyzed C-H arylation reaction of aliphatic aldehyde by calix [4] arene amide compound |
| CN113731506B (en) * | 2021-09-28 | 2023-05-26 | 常州大学 | Method for assisting palladium-catalyzed fatty aldehyde C-H arylation reaction by calix [4] arene amide compound |
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