CN115043704A - High-optical-purity gem-difluoro cyclopropane, preparation method and application - Google Patents
High-optical-purity gem-difluoro cyclopropane, preparation method and application Download PDFInfo
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- CN115043704A CN115043704A CN202210886834.1A CN202210886834A CN115043704A CN 115043704 A CN115043704 A CN 115043704A CN 202210886834 A CN202210886834 A CN 202210886834A CN 115043704 A CN115043704 A CN 115043704A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical compound PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000003446 ligand Substances 0.000 claims abstract description 22
- 229910052703 rhodium Inorganic materials 0.000 claims abstract description 21
- 239000010948 rhodium Substances 0.000 claims abstract description 21
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims abstract description 19
- 229910052751 metal Inorganic materials 0.000 claims abstract description 16
- 239000002184 metal Substances 0.000 claims abstract description 16
- 230000003287 optical effect Effects 0.000 claims abstract description 15
- GPCDGGKVBPVZCT-UHFFFAOYSA-N 1,1-difluorocyclopropane Chemical compound FC1(F)CC1 GPCDGGKVBPVZCT-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000000654 additive Substances 0.000 claims abstract description 13
- 230000000996 additive effect Effects 0.000 claims abstract description 13
- 238000010438 heat treatment Methods 0.000 claims abstract description 5
- 239000002904 solvent Substances 0.000 claims abstract description 5
- 238000002156 mixing Methods 0.000 claims abstract description 4
- 239000000203 mixture Substances 0.000 claims abstract description 4
- 238000003756 stirring Methods 0.000 claims abstract description 4
- -1 rhodium metal compound Chemical class 0.000 claims description 40
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 24
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 23
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
- 229910052731 fluorine Inorganic materials 0.000 claims description 20
- 125000001153 fluoro group Chemical group F* 0.000 claims description 18
- 229910052801 chlorine Inorganic materials 0.000 claims description 15
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 14
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 12
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- AZEBUSRDBBMQGF-UHFFFAOYSA-N bis(3,5-ditert-butyl-4-methoxyphenyl)phosphane Chemical compound C1=C(C(C)(C)C)C(OC)=C(C(C)(C)C)C=C1PC1=CC(C(C)(C)C)=C(OC)C(C(C)(C)C)=C1 AZEBUSRDBBMQGF-UHFFFAOYSA-N 0.000 claims description 11
- 125000005504 styryl group Chemical group 0.000 claims description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 9
- UAJRSHJHFRVGMG-UHFFFAOYSA-N 1-ethenyl-4-methoxybenzene Chemical compound COC1=CC=C(C=C)C=C1 UAJRSHJHFRVGMG-UHFFFAOYSA-N 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 8
- VYXHVRARDIDEHS-UHFFFAOYSA-N 1,5-cyclooctadiene Chemical compound C1CC=CCCC=C1 VYXHVRARDIDEHS-UHFFFAOYSA-N 0.000 claims description 6
- 239000004912 1,5-cyclooctadiene Substances 0.000 claims description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 6
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims description 6
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 239000005977 Ethylene Substances 0.000 claims description 4
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- MZJYQXPULRLGCA-UHFFFAOYSA-N 1,1-dichlorocyclopropane Chemical group ClC1(Cl)CC1 MZJYQXPULRLGCA-UHFFFAOYSA-N 0.000 claims description 3
- XSRWPJFTHDOKTA-UHFFFAOYSA-M [Rh]Cl.C1CC=CCCC=C1 Chemical class [Rh]Cl.C1CC=CCCC=C1 XSRWPJFTHDOKTA-UHFFFAOYSA-M 0.000 claims description 3
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims description 3
- FEQPHYCEZKWPNE-UHFFFAOYSA-K trichlororhodium;triphenylphosphane Chemical compound Cl[Rh](Cl)Cl.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 FEQPHYCEZKWPNE-UHFFFAOYSA-K 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 abstract description 10
- 230000000975 bioactive effect Effects 0.000 abstract description 6
- 238000001228 spectrum Methods 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 125000003118 aryl group Chemical group 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 4
- 150000001942 cyclopropanes Chemical class 0.000 description 4
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 102000004882 Lipase Human genes 0.000 description 2
- 108090001060 Lipase Proteins 0.000 description 2
- 239000004367 Lipase Substances 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 238000004296 chiral HPLC Methods 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 235000019421 lipase Nutrition 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- LYXHWHHENVLYCN-QMDOQEJBSA-N (1z,5z)-cycloocta-1,5-diene;rhodium;tetrafluoroborate Chemical compound [Rh].F[B-](F)(F)F.C\1C\C=C/CC\C=C/1.C\1C\C=C/CC\C=C/1 LYXHWHHENVLYCN-QMDOQEJBSA-N 0.000 description 1
- 238000006043 Intramolecular Michael addition reaction Methods 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000009881 electrostatic interaction Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- MJEMIOXXNCZZFK-UHFFFAOYSA-N ethylone Chemical compound CCNC(C)C(=O)C1=CC=C2OCOC2=C1 MJEMIOXXNCZZFK-UHFFFAOYSA-N 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000006459 hydrosilylation reaction Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000008204 material by function Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 229940121649 protein inhibitor Drugs 0.000 description 1
- 239000012268 protein inhibitor Substances 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/35—Preparation of halogenated hydrocarbons by reactions not affecting the number of carbon or of halogen atoms in the reaction
- C07C17/358—Preparation of halogenated hydrocarbons by reactions not affecting the number of carbon or of halogen atoms in the reaction by isomerisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C23/00—Compounds containing at least one halogen atom bound to a ring other than a six-membered aromatic ring
- C07C23/18—Polycyclic halogenated hydrocarbons
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a high-optical pure gem-difluoro cyclopropane, a preparation method and application thereof, which comprise the following steps: step 1: fully mixing racemic difluoro cyclopropane, metal rhodium, diphosphine ligand and additive; the molar ratio of the metal rhodium to the diphosphine ligand is 1: 0.5-2; the molar ratio of the additive to the metal rhodium or diphosphine ligand is as follows: 0-50: 1. Step 2: adding a solvent into the mixture obtained in the step 1, stirring and heating, fully reacting, and purifying to obtain high-optical-purity gem-difluoro cyclopropane; the invention can prepare high optical purity gem-difluorocyclopropane under mild conditions, and the preparation method is simple; the obtained high optical purity gem-difluoro cyclopropane contains a quaternary carbon center and a tertiary carbon center; the obtained high optical purity gem-difluoro cyclopropane can be used as an intermediate to be introduced into bioactive molecules.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, and particularly relates to high-optical-purity gem-difluoro cyclopropane, a preparation method and application thereof.
Background
Cyclopropyl is a common structure in organic compounds, and is widely applied to relevant fields of chemistry, materials science, biology and the like. Cyclopropyl, as the smallest cyclic unit and a rigid cyclic structure, has a unique electronic structure that can modulate the chemical properties of the molecule to show specific reactivity. Over the past several decades, halogenated cyclopropanes have attracted considerable attention in the fields of organic chemistry, bio-organic chemistry, medicinal chemistry and agrochemical. Halogenated cyclopropane, oil and gas are fluorinated cyclopropane, which can be used not only to prepare bioactive substances and functional materials, but also as precursors of other fluorine-containing compounds. The fluorine atom is capable of forming a stable chemical bond with carbon and can profoundly change the physicochemical properties of the parent molecule due to the high electronegativity of the fluorine atom. In biologically active molecules, the fluorine substituents can greatly affect the charge distribution, electrostatic interaction and solubility of the molecule. Introduction of fluorine-containing groups into natural compounds has been widely used in new drug design and pesticide development, and the use of bioactive molecules containing at least one fluorine atom has been very widespread. In some drug development, the introduction of geminal difluorocyclopropyl into a protein inhibitor can significantly improve the oral bioavailability of the inhibitor and can also significantly reduce the cytotoxicity of the inhibitor.
Geminal difluorocyclopropane itself contains at least one chiral carbon, so that it is often necessary for the starting material to be a single configurational molecule when it is put into use. Although there are many methods for preparing racemic geminal difluorocyclopropane, most of them are limited to the in-situ generation of geminal difluorocarbene precursors for the addition of olefins, so only racemic geminal difluorocyclopropane can be prepared. The current asymmetric synthesis of gem-difluorocyclopropane can only be realized in some substrates of specific structure. Although the chiral column is used for resolving racemic geminal difluorocyclopropane, the geminal difluorocyclopropane with a single configuration can also be prepared, but the method has low efficiency and large limitation.
The existing synthesis methods, such as asymmetric difluorocyclopropane using chiral radial group to induce special olefin substrate or selective hydrolysis of gem-difluorocyclopropane using lipase catalysis, such as chiral radial group to induce diastereoselective intramolecular michael addition of enolate and lipase catalysis kinetic resolution of diacetate, synthesize gem-difluorocyclopropane containing certain specific structure. However, the method can only be used for preparing gem-difluoro cyclopropane containing special structures, such as ester groups, amide groups and the like; the obtained geminal difluorocyclopropane has lower optical purity and lower application value.
Aryl gem-difluorocyclopropanes can be prepared, for example, by using copper and a chiral ligand to catalyze the asymmetric hydrogenation of aryl gem-difluoropropene. However, the method can only be used for preparing aryl-containing gem-difluoro cyclopropane, and is difficult to be applied to the synthesis of complex molecules; the obtained geminal difluorocyclopropane has low optical purity and low application value. The silicon-based gem-difluorinated cyclopropane can also be prepared by catalyzing asymmetric hydrosilylation of aryl gem-difluorocyclopropene by using copper and a chiral ligand. However, this procedure can likewise only be used for the preparation of gem-difluorocyclopropanes containing aryl and silyl groups. The applicable substrate range is smaller, the geminal difluorocyclopropane can be prepared less, and racemization is easy to occur. The corresponding gem-difluoro cyclopropyl carboxylic ester can be prepared by catalyzing asymmetric hydrogenation of gem-difluoro propenyl carboxylic ester by using a chiral ruthenium catalyst. However, the method has insufficient substrate universality and is sensitive to the functional groups and the structure of the substrate.
Disclosure of Invention
The invention provides high-optical-purity gem-difluoro cyclopropane, a preparation method and application thereof aiming at the problems in the prior art.
The technical scheme adopted by the invention is as follows:
a preparation method of high optical purity gem-difluoro cyclopropane comprises the following steps:
step 1: fully mixing racemic difluoro cyclopropane, metal rhodium, diphosphine ligand and additive; the molar ratio of the metal rhodium to the diphosphine ligand is 1: 0.5-2; the molar ratio of the additive to the metal rhodium or diphosphine ligand is as follows: 0-50: 1.
Step 2: and (2) adding a solvent into the mixture obtained in the step (1), stirring and heating, fully reacting, and purifying to obtain the high-optical-purity gem-difluoro cyclopropane.
Further, the metal rhodium is a monovalent rhodium metal compound, and is one of the following compounds: tetracarbonyldirhodium dichloride, tetravinyldirhodium dichloride, triphenylphosphine rhodium chloride, (1, 5-cyclooctadiene) chlororhodium (I) dimer, (1, 5-cyclooctadiene) ((R) - (-) -5,5 '-bis [ bis (3, 5-di-tert-butyl-4-methoxyphenyl) phosphine ] -4,4' -bis-1, 3-benzodioxolane) rhodium tetrafluoroborate (I), bis (1, 5-cyclooctadiene) rhodium tetrafluoroborate (I).
Further, the diphosphine ligand is one of the following ligands: r- (+) -1,1' -binaphthyl-2, 2' -bisdiphenylphosphine, S- (-) -1,1' -binaphthyl-2, 2' -bisdiphenylphosphine, S- (+) -1,1' -binaphthyl-2, 2' -bisdiphenylphosphine, S- (-) -1,1' -binaphthyl-2, 2' -bisdiphenylphosphine, (R) - (-) -5,5' -bis [ bis (3, 5-di-tert-butyl-4-methoxyphenyl) phosphine ] -4,4' -bis-1, 3-benzodioxolane, (S) - (-) -5,5' -bis [ bis (3, 5-di-tert-butyl-4-methoxyphenyl) phosphine ] -4,4' -bis-1, 3-benzodioxolane.
Further, the additive is aromatic hydrocarbon or aryl ethylene and is one of the following substances: anisole, phenol, styrene, p-methoxystyrene.
Further, the reaction time in the step 2 is 0.5-12 hours, and the reaction temperature is as follows: 70-120 ℃.
A high optical purity gem-dichloro cyclopropane, the structure of which is any one of the following:
wherein: r 1 Is one of hydrogen atom, ethyl, n-hexyl, phenyl, benzyl and styryl; r 2 Is one of hydrogen atom, methyl, ethyl, fluorine atom, chlorine atom, hydroxyl, methoxyl and formylmethoxyl; r 3 Is one of hydrogen atom, methyl, ethyl, fluorine atom, chlorine atom, bromine atom, phenyl, hydroxyl, methoxyl, formyl methoxyl, isopropoxy, benzyloxy and acetamido; r 4 Is one of hydrogen atom, methyl, ethyl, fluorine atom, chlorine atom, bromine atom, phenyl, hydroxyl, methoxyl, formyl methoxyl, isopropoxy, benzyloxy and acetamido; r 5 Is one of hydrogen atom, methyl, ethyl, fluorine atom, chlorine atom, bromine atom, phenyl, hydroxyl, methoxyl, formyl methoxyl, isopropoxy, benzyloxy and acetamido; r 6 Is one of hydrogen atom, ethyl, n-hexyl, phenyl, benzyl and styryl; r 7 Is a hydrogen atom, methyl, ethylOne of group, fluorine atom, chlorine atom, bromine atom, phenyl group, hydroxyl group, methoxyl group, formyl methoxyl group, isopropoxy group, benzyloxy group and acetamido group; r is 8 Is one of hydrogen atom, ethyl, n-hexyl, phenyl, benzyl and styryl.
The application of high-optical-purity dichloro cyclopropane, which is introduced into a bioactive molecule as an intermediate.
The invention has the beneficial effects that:
(1) the invention can prepare high optical purity gem-difluorocyclopropane under mild conditions, and the preparation method is simple;
(2) the high-optical purity gem-difluorocyclopropane obtained by the invention contains a quaternary carbon center and a tertiary carbon center;
(3) the invention can adopt a simple preparation method to obtain the high-optical-purity gem-difluorocyclopropane, and the obtained high-optical-purity gem-difluorocyclopropane can be used as an intermediate to be introduced into bioactive molecules.
Drawings
FIG. 1 is a reaction formula in the preparation method of the present invention.
FIG. 2 shows a nuclear magnetic spectrum hydrogen spectrum of the product obtained in example 1 of the present invention.
FIG. 3 is a nuclear magnetic spectrum carbon spectrum of the product obtained in example 1 of the present invention.
FIG. 4 is a nuclear magnetic spectrum fluorine spectrum of the product obtained in example 1 of the present invention.
FIG. 5 is a high performance liquid chromatogram of the product obtained in example 1 of the present invention.
FIG. 6 is a high performance liquid chromatogram of the starting material in example 1 of the present invention.
FIG. 7 shows a nuclear magnetic spectrum hydrogen spectrum of the product obtained in example 2 of the present invention.
FIG. 8 is a nuclear magnetic spectrum carbon spectrum of the product obtained in example 2 of the present invention.
FIG. 9 shows the NMR spectra of the product obtained in example 2 of the present invention.
FIG. 10 is a high performance liquid chromatogram of the product obtained in example 2 of the present invention.
FIG. 11 is a high performance liquid chromatogram of the starting material in example 2 of the present invention.
FIG. 12 is a schematic diagram of the process of synthesizing biologically active molecules from high optical purity gem-difluorocyclopropane obtained by the present invention.
Detailed Description
The invention is further described with reference to the following figures and specific examples.
As shown in fig. 1, a preparation method of high optical purity gem-difluoro cyclopropane comprises the following steps:
step 1: fully mixing racemic difluoro cyclopropane, metal rhodium, diphosphine ligand and additive; the molar ratio of the metal rhodium to the diphosphine ligand is 1: 0.5-2; the molar ratio of the additive to the metal rhodium or diphosphine ligand is as follows: 0-50: 1.
The rhodium metal is a monovalent rhodium metal compound and is one of the following compounds: dicarbonyldirhodium chloride, tetravinyldirhodium dichloride, triphenylphosphine rhodium chloride, (1, 5-cyclooctadiene) chlororhodium (I) dimer, (1, 5-cyclooctadiene) ((R) - (-) -5,5 '-bis [ bis (3, 5-di-tert-butyl-4-methoxyphenyl) phosphine ] -4,4' -bis-1, 3-benzodioxolane) rhodium tetrafluoroborate (I), bis (1, 5-cyclooctadiene) rhodium tetrafluoroborate (I). The diphosphine ligand is one of the following ligands: r- (+) -1,1' -binaphthyl-2, 2' -bisdiphenylphosphine, S- (-) -1,1' -binaphthyl-2, 2' -bisdiphenylphosphine, S- (+) -1,1' -binaphthyl-2, 2' -bisdiphenylphosphine, S- (-) -1,1' -binaphthyl-2, 2' -bisdiphenylphosphine, (R) - (-) -5,5' -bis [ bis (3, 5-di-tert-butyl-4-methoxyphenyl) phosphine ] -4,4' -bis-1, 3-benzodioxolane, (S) - (-) -5,5' -bis [ bis (3, 5-di-tert-butyl-4-methoxyphenyl) phosphine ] -4,4' -bis-1, 3-benzodioxolane.
The additive is aromatic hydrocarbon or aryl ethylene, and is one of the following substances: anisole, phenol, styrene, p-methoxystyrene.
Step 2: and (2) adding a solvent into the mixture obtained in the step (1), stirring and heating, fully reacting, and purifying to obtain the high-optical-purity gem-difluoro cyclopropane. The racemic gem-difluorocyclopropane raw material is subjected to kinetic resolution under the heating condition to prepare the high-optical-purity gem-difluorocyclopropane. The structure is as follows:
wherein: r 1 Is one of hydrogen atom, ethyl, n-hexyl, phenyl, benzyl and styryl; r 2 Is one of hydrogen atom, methyl, ethyl, fluorine atom, chlorine atom, hydroxyl, methoxyl and formylmethoxyl; r 3 Is one of hydrogen atom, methyl, ethyl, fluorine atom, chlorine atom, bromine atom, phenyl, hydroxyl, methoxyl, formyl methoxyl, isopropoxy, benzyloxy and acetamido; r 4 Is one of hydrogen atom, methyl, ethyl, fluorine atom, chlorine atom, bromine atom, phenyl, hydroxyl, methoxyl, formyl methoxyl, isopropoxy, benzyloxy and acetamido; r 5 Is one of hydrogen atom, methyl, ethyl, fluorine atom, chlorine atom, bromine atom, phenyl, hydroxyl, methoxyl, formyl methoxyl, isopropoxy, benzyloxy and acetamido; r 6 Is one of hydrogen atom, ethyl, n-hexyl, phenyl, benzyl and styryl; r 7 Is one of hydrogen atom, methyl, ethyl, fluorine atom, chlorine atom, bromine atom, phenyl, hydroxyl, methoxyl, formyl methoxyl, isopropoxy, benzyloxy and acetamido; r 8 Is one of hydrogen atom, ethyl, n-hexyl, phenyl, benzyl and styryl.
The molar ratio of the metal rhodium to the diphosphine ligand is 1: 0.5-2, and the optimal molar ratio is 1: 1; the molar ratio of the racemic gem-difluorocyclopropane to the additive aromatic hydrocarbon (aryl ethylene) is 1: 0-10, and the optimal molar ratio is 1: 2.
In the step 1, the concentration of the reactant in the reaction process is 0.1-5.0 mol/L, and the optimal concentration is 1.0 mol/L. In the case of preparing the general formula (I) or (II) in the step 2, the reaction time is 0.5 to 12 hours, preferably 1 hour. In the preparation of the general formula (III) or (IV), the reaction time is from 0.5 to 12 hours, preferably 7 hours.
The most preferred catalyst for the preparation of formula (I) or (II) is rhodium [ (1, 5-cyclooctadiene) ((R) - (-) -5,5 '-bis [ bis (3, 5-di-tert-butyl-4-methoxyphenyl) phosphine ] -4,4' -bis-1, 3-benzodioxolane) tetrafluoroborate (I) ], and the most preferred catalyst for the preparation of (III) or (IV) is rhodium [ bis (1, 5-cyclooctadiene) tetrafluoroborate (I) ].
Example 1
A preparation method of high optical purity gem-difluoro cyclopropane comprises the following steps:
step 1: a4 mL screw vial was charged with a magnetic stirrer, styryl gem-difluorocyclopropane 0.2mmol, p-methoxystyrene 0.2mmol, [ (1, 5-cyclooctadiene) ((R) - (-) -5,5 '-bis [ bis (3, 5-di-tert-butyl-4-methoxyphenyl) phosphine ] -4,4' -bis-1, 3-benzodioxolane) tetrafluoroborate rhodium (I) ]0.006mmol, and tetrahydrofuran 0.6mL in that order in a nitrogen blanketed glove box;
step 2: the screw cap was closed and removed from the glove box, and placed on a magnetic stirrer and heated to 90 ℃ and stirred for 1 hour. Transferring the obtained reaction solution to silica gel chromatographic column, eluting with organic solvent PE to obtain colorless liquid (R) f 0.3), yield 44% (17.2 mg).
The resulting product has the structure shown below:
the nuclear magnetic spectrum is shown in FIGS. 2, 3 and 4, and shown in FIG. 2 1 H NMR(400MHz,Chloroform-d)δ7.36(d,J＝6.8Hz,2H)，7.31(t,J＝7.8Hz,2H)，7.23(t,J＝6.7Hz,1H)，6.50(d,J＝16.1Hz,1H)，6.07(d,J＝16.1Hz,1H)，1.49(ddd,J＝13.3,7.6,4.8Hz,1H)，1.44(t,J＝2.2Hz,3H)，1.36(ddd,J＝12.9,7.3,5.4Hz,1H)。
As shown in figure 3 of the drawings, 13 C NMR(101MHz,Chloroform-d)δ136.83，129.79,128.60,127.92(dd,J＝6.8,2.8Hz)，127.44,126.05,115.95(dd,J＝293.5,288.8Hz)，28.61(dd,J＝11.4,10.0Hz)，24.12(dd,J＝10.6,8.2Hz),15.34(d,J＝6.4Hz)。
as shown in figure 4 of the drawings, 19 F NMR(376MHz,Chloroform-d)δ-135.10(dd,J＝151.9,13.5Hz)，-136.28(dd,J＝152.0,13.3Hz)。
as shown in FIG. 5, Chiral HPLC (Chiralpak OD-H, Hexane: i-PrOH ═ 100:0,1mL/min,254nm, t major ＝13.0min,t minor ＝12.2min).98％ee。
As shown in FIG. 6, HRMS (ESI, m/z): calcd for C 12 H 13 F 2 +[M+H]+195.0980,found 195.0983。
Example 2
A preparation method of high optical purity gem-difluoro cyclopropane comprises the following steps:
step 1: a magnetic stirrer, 0.2mmol of 4-biphenylyl gem-difluorocyclopropane, 0.2mmol of p-anisole, 0.004mmol of [ bis (1, 5-cyclooctadiene) rhodium (I) tetrafluoroborate (R- (+) -1,1 '-binaphthyl-2, 2' -bis-diphenylphosphine, 0.004mmol and 0.2mL of trifluorotoluene are sequentially added into a 4mL screw-mouth vial in a nitrogen-protected glove box;
step 2: the screw cap was closed and removed from the glove box and placed on a magnetic stirrer and stirred for 7 hours. Transferring the obtained reaction solution to silica gel chromatographic column, eluting with organic solvent PE to obtain colorless liquid (R) f 0.25), yield 45% (20.7 mg).
The resulting product has the following structure:
the nuclear magnetic spectrum of the product is shown in figures 7, 8 and 9, as shown in figure 7, 1 H NMR(400MHz,Chloroform-d)δ7.63–7.51(m,4H)，7.47–7.37(m,2H),7.36–7.31(m,1H)，7.29(d,J＝8.7Hz,2H),2.78(ddd,J＝13.2,11.7,8.1Hz,1H)，1.84(dddd,J＝12.7,11.7,7.9,4.9Hz,1H)，1.65(dtd,J＝12.7,8.0,3.9Hz,1H)。
as shown in figure 8 of the drawings, 13 C NMR(101MHz,Chloroform-d)δ140.60,140.10,132.71,128.78,128.40,127.33,127.18,127.02,112.61(dd,J＝287.2,284.0Hz)，26.92(t,J＝11.5Hz)，17.11(t,J＝10.5Hz)。
as shown in figure 9 of the drawings, 19 F NMR(376MHz,Chloroform-d)δ-125.62(dtd,J＝153.4,13.1,4.2Hz),-142.06(ddd,J＝153.5,12.7,4.6Hz)。
as shown in FIGS. 10 and 11, Chiral HPLC (Chiralpak AD-H, Hexane: i-PrOH ═ 100:0,1mL/min,254nm, t major ＝9.9min,t minor ＝8.8min).99.2％ee。
The high-optical purity gem-difluoro cyclopropane obtained by the method can be used as an intermediate to be introduced into bioactive molecules. The reaction process is shown in FIG. 12.
The high-optical pure gem-difluorocyclopropane prepared by kinetic resolution is a general preparation method which is difficult to synthesize. The high-optical-purity gem-difluoro cyclopropane containing a quaternary carbon or tertiary carbon center can be efficiently prepared; and the used catalyst, ligand, additive, solvent and raw material are all commercially available or are easy to prepare, and the reaction condition is mild, simple and easy to operate. Can prepare high optical purity gem-difluoro cyclopropane in a large quantity in a single batch.
Claims (7)
1. A preparation method of high optical purity gem-difluorocyclopropane is characterized by comprising the following steps:
step 1: fully mixing racemic difluoro cyclopropane, metal rhodium, diphosphine ligand and additive; the molar ratio of the metal rhodium to the diphosphine ligand is 1: 0.5-2; the molar ratio of the additive to the metal rhodium or diphosphine ligand is 0-50: 1.
Step 2: and (2) adding a solvent into the mixture obtained in the step (1), stirring and heating, fully reacting, and purifying to obtain the high-optical-purity gem-difluoro cyclopropane.
2. The method for preparing high optical purity gem-difluorocyclopropane according to claim 1, wherein the rhodium metal is a monovalent rhodium metal compound selected from the group consisting of: dicarbonyldirhodium chloride, tetravinyldirhodium dichloride, triphenylphosphine rhodium chloride, (1, 5-cyclooctadiene) chlororhodium (I) dimer, (1, 5-cyclooctadiene) ((R) - (-) -5,5 '-bis [ bis (3, 5-di-tert-butyl-4-methoxyphenyl) phosphine ] -4,4' -bis-1, 3-benzodioxolane) rhodium tetrafluoroborate (I), bis (1, 5-cyclooctadiene) rhodium tetrafluoroborate (I).
3. The process according to claim 1, wherein the bisphosphine ligand is one of the following ligands: r- (+) -1,1' -binaphthyl-2, 2' -bisdiphenylphosphine, S- (-) -1,1' -binaphthyl-2, 2' -bisdiphenylphosphine, S- (+) -1,1' -binaphthyl-2, 2' -bisdiphenylphosphine, S- (-) -1,1' -binaphthyl-2, 2' -bisdiphenylphosphine, (R) - (-) -5,5' -bis [ bis (3, 5-di-tert-butyl-4-methoxyphenyl) phosphine ] -4,4' -bis-1, 3-benzodioxolane, (S) - (-) -5,5' -bis [ bis (3, 5-di-tert-butyl-4-methoxyphenyl) phosphine ] -4,4' -bis-1, 3-benzodioxolane.
4. The method for preparing high-optical-purity gem-dichloro-cyclopropane according to claim 1, wherein the additive is aromatic hydrocarbon or aryl ethylene and is one of the following substances: anisole, phenol, styrene, p-methoxystyrene.
5. The method for preparing high-optical-purity gem-dichloro-cyclopropane according to claim 1, wherein the reaction time in the step 2 is 0.5-12 hours, and the reaction temperature is: 70-120 ℃.
6. The high-optical-purity gem-dichloro cyclopropane obtained by the preparation method according to any one of claims 1 to 5 is characterized by having a structure of any one of the following:
formula (I)
Formula (II)
Formula (III)
And formula (IV)
Wherein: r 1 Is one of hydrogen atom, ethyl, n-hexyl, phenyl, benzyl and styryl; r 2 Is hydrogen atom, methyl, ethyl, fluorineOne of atom, chlorine atom, hydroxyl, methoxyl and formylmethoxyl; r 3 Is one of hydrogen atom, methyl, ethyl, fluorine atom, chlorine atom, bromine atom, phenyl, hydroxyl, methoxyl, formyl methoxyl, isopropoxy, benzyloxy and acetamido; r 4 Is one of hydrogen atom, methyl, ethyl, fluorine atom, chlorine atom, bromine atom, phenyl, hydroxyl, methoxyl, formyl methoxyl, isopropoxy, benzyloxy and acetamido; r 5 Is one of hydrogen atom, methyl, ethyl, fluorine atom, chlorine atom, bromine atom, phenyl, hydroxyl, methoxyl, formyl methoxyl, isopropoxy, benzyloxy and acetamido; r 6 Is one of hydrogen atom, ethyl, n-hexyl, phenyl, benzyl and styryl; r 7 Is one of hydrogen atom, methyl, ethyl, fluorine atom, chlorine atom, bromine atom, phenyl, hydroxyl, methoxyl, formyl methoxyl, isopropoxy, benzyloxy and acetamido; r 8 Is one of hydrogen atom, ethyl, n-hexyl, phenyl, benzyl and styryl.
7. The use of a highly optically pure geminal dichlorocyclopropane according to claim 6, wherein the highly optically pure geminal dichlorocyclopropane is incorporated into a biologically active molecule as an intermediate.
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