Synthesis of chiral amine compounds by organocatalytic aromatization-promoted polarity reversal reaction of imines

Abstract

The application belongs to the field of chemical synthesis. The application provides an organic catalytic method for forming a compound containing a chiral C-N bond and an organic catalytic method for forming a compound containing a C-N axis chiral (hetero) aryl skeleton. The method uses a specific chiral phosphoric acid as a catalyst to obtain a chiral amine structure or a C-N axis chiral aryl skeleton with potential application value. The method has high yield of the obtained product and good enantioselectivity.

Description

Technical Field

[0001] This invention relates to the field of catalyst technology, specifically to organocatalytic aromatization promoting the polarity reversal reaction of imines to synthesize chiral amine compounds. Background Technology

[0002] Chiral amines are important structural units in bioactive molecules, natural products, intermediates, and decomposition agents, and have wide applications in the synthesis of pharmaceuticals, agrochemicals, and materials, as well as in asymmetric catalysis. For example, analgesics such as morphine and tramadol, antidepressants such as sertraline, and antithrombotic drugs such as clopidogrel all contain chiral amine fragments. However, the synthesis of chiral amines has long been a challenge in synthetic chemistry. Nitrogen-centered radicals are highly unstable and easily quenched by the extraction of a hydrogen atom. Furthermore, without organocatalysts or transition metal catalysts to bind groups, it is difficult to control the chiral addition of nitrogen-centered radicals to unsaturated bonds, especially when the target chiral center is far from the reaction center.

[0003] Pumpolung can alter the intrinsic polarity of the original reaction center and chemical bonds, providing a new pathway for the synthesis of organic compounds. The most commonly used polarity-inverting groups are acyl anion analogs, which convert the acyl group to a thioacetal via the traditional Corey-Seebach reaction, or convert the originally electrophilic carbonyl carbon to a nucleophilic carbonyl carbon, reacting with a nitrogen-containing heterocyclic carbene intermediate. In 2015, Professor Deng Li first reported in the top international journal *Nature* the asymmetric umpolung reaction of imines with unsaturated aldehydes catalyzed by phase-transfer catalysts (PTCs), constructing chiral multifunctional compounds containing both amino and aldehyde groups with very high enantiomeric selectivity. Later, his team reported in the *Journal of the American Chemical Society* the asymmetric umpolung reaction of imines with relatively less reactive unsaturated ketones catalyzed by a phase-transfer catalyst, efficiently constructing organic chiral synthons containing both amino and ketone carbonyl groups. However, there is still a great need for more diverse construction methods for chiral amines. Summary of the Invention

[0004] To address the aforementioned technical problems, this invention provides an organocatalytic method for forming compounds containing chiral CN bonds and an organocatalytic method for forming CN-axis-containing chiral (hetero)aryl skeleton compounds. These methods yield high product yields and exhibit ideal enantioselectivity.

[0005] Specifically, on one hand, the present invention provides an organocatalytic method for forming compounds containing chiral CN bonds, comprising reacting N-acylindolide (E-1) and hydroxyaryl group (N-1) in a solvent under chiral phosphoric acid catalysis to form compounds containing chiral CN bonds;

[0006]

[0007] The chiral phosphoric acid is selected from: (R)-C2, (R)-C3, (R)-C4, and (R)-C5.

[0008]

[0009] Cy stands for cyclohexyl, Cp for cyclopentadienyl, iPr for isopropyl, and tBu for tert-butyl.

[0010] Among them, R 1 Each is independently selected from: H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl and substituted or unsubstituted heteroarylalkyl;

[0011] R 5 Selected from: -C(=O)R 2 ;R 2 Each is independently selected from: substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl and substituted or unsubstituted heteroarylalkyl;

[0012] R 3 Selected from: substituted or unsubstituted aryl groups and substituted or unsubstituted heteroaryl groups;

[0013] R 4 Each is independently selected from: substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl and substituted or unsubstituted heteroarylalkyl;

[0014] n can be 0, 1, 2, 3, or 4;

[0015] m can be 0, 1, 2, 3, or 4.

[0016] In some embodiments,

[0017] R 1 Each is independently selected from: H, substituted or unsubstituted C. 1-10 Alkyl, substituted or unsubstituted heteroalkyl containing 1-10 carbons and 1-3 heteroatoms, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted 5-10 membered heterocyclic groups, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 heteroaryl, substituted or unsubstituted C6-10 Aryl C 1-10 Alkyl and substituted or unsubstituted 5-10 membered heteroaryl C 1-10 alkyl;

[0018] R 5 Selected from: -C(=O)R 2 ;R 2 Each is independently selected from: substituted or unsubstituted C 1-10 Alkyl, substituted or unsubstituted heteroalkyl containing 1-10 carbons and 1-3 heteroatoms, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted 5-10 membered heterocyclic groups, substituted or unsubstituted aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 6-10 Aryl C 1-10 Alkyl and substituted or unsubstituted 5-10 membered heteroaryl C 1-10 alkyl;

[0019] R 3 Selected from: substituted or unsubstituted C 6-10 Aryl and substituted or unsubstituted 5-10 membered heteroaryl groups;

[0020] R 4 Each is independently selected from: substituted or unsubstituted C 1-10 Alkyl, substituted or unsubstituted heteroalkyl containing 1-10 carbons and 1-3 heteroatoms, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted 5-10 membered heterocyclic groups, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 heteroaryl, substituted or unsubstituted C 6-10 Aryl C 1-10 Alkyl and substituted or unsubstituted 5-10 membered heteroaryl C 1-10 alkyl.

[0021] In some embodiments, the solvent for the reaction is one or more combinations of dichloromethane, dichloroethane, trichloromethane, and toluene.

[0022] In some embodiments, the molar ratio of the N-acylindolide (E-1) to the hydroxyaryl group (N-1) is 2:(2.5-5).

[0023] In some embodiments, the molar ratio of the N-acylindolide (E-1) to the hydroxyaryl group (N-1) is 2:(3-4).

[0024] In some embodiments, the amount of chiral phosphoric acid is 2 to 15% molar monomass, with the molar amount of N-acylindoimide (E-1) as unit 1.

[0025] In some embodiments, the amount of chiral phosphoric acid is 5-10% molar monomass, with the molar amount of N-acylindoimide (E-1) as unit 1.

[0026] In some embodiments, the reaction temperature is -40°C to room temperature; the reaction time is 5 to 20 minutes.

[0027] In some embodiments, the reaction temperature is -40°C to 0°C; the reaction time is 10-20 minutes.

[0028] On the other hand, the present invention also provides an organocatalytic method for forming a CN-axis-containing chiral aryl skeleton compound, comprising reacting N-acyl iminoquinone (E-2) and amino aryl (N-2) in a solvent under chiral phosphoric acid catalysis to form a CN-axis-containing chiral aryl skeleton compound;

[0029]

[0030] The chiral phosphoric acid is selected from: (R)-C6, (R)-C7, (R)-C8, (R)-C9, (R)-C10 and (R)-C11.

[0031]

[0032] Ph stands for phenyl, and tBu stands for tert-butyl.

[0033] Among them, R a Selected from: substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl and substituted or unsubstituted heteroarylalkyl;

[0034] R b Each is independently selected from: H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl and substituted or unsubstituted heteroarylalkyl;

[0035] R e Selected from: substituted or unsubstituted alkyl groups and substituted or unsubstituted cycloalkyl groups;

[0036] R is selected from: substituted or unsubstituted aryl groups and substituted or unsubstituted heteroaryl groups;

[0037] X is selected from: H, Cl, and Br;

[0038] q can be 0, 1, 2, 3 or 4.

[0039] In some embodiments, R a Selected from: substituted or unsubstituted C 1-10 Alkyl, substituted or unsubstituted heteroalkyl containing 1-10 carbons and 1-3 heteroatoms, C 3-10 Cycloalkyl, substituted or unsubstituted 5-10 membered heterocyclic groups, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 heteroaryl, substituted or unsubstituted C 6-10 Aryl C 1-10 Alkyl and substituted or unsubstituted 5-10 membered heteroaryl C 1-10 alkyl;

[0040] R b Each is independently selected from: H, halogen, substituted or unsubstituted C. 1-10 Alkyl, substituted or unsubstituted C 1-10 Alkoxy, substituted or unsubstituted heteroalkyl containing 1-10 carbons and 1-3 heteroatoms, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted 5-10 membered heterocyclic groups, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 heteroaryl, substituted or unsubstituted C 6-10 Aryl C 1-10 Alkyl and substituted or unsubstituted 5-10 membered heteroaryl C 1-10 alkyl;

[0041] R e Selected from: substituted or unsubstituted C 1-10 Alkyl and substituted or unsubstituted C 3-10 cycloalkyl;

[0042] R is selected from: substituted or unsubstituted C 6-10 Aryl and substituted or unsubstituted 5-10 heteroaryl groups.

[0043] On the other hand, the present invention also provides an organocatalytic method for forming a CN-axis-containing chiral aryl skeleton compound, comprising reacting N-acyl iminoquinone (E-3) and an indole derivative (N-3) in a solvent under chiral phosphoric acid catalysis to form a CN-axis-containing chiral aryl skeleton compound;

[0044]

[0045] The chiral phosphoric acid is (R)-C12 and has the following structure:

[0046]

[0047] Among them, R aSelected from: substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl and substituted or unsubstituted heteroarylalkyl;

[0048] R c Each is independently selected from: substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl and substituted or unsubstituted heteroarylalkyl;

[0049] R d Each is independently selected from: H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl and substituted or unsubstituted heteroarylalkyl;

[0050] When R d In R c When adjacent, any location can be chosen, R d and R c Together with the atoms they are attached to, they form substituted or unsubstituted aryl groups or substituted or unsubstituted heteroaryl groups;

[0051] R e Selected from: substituted or unsubstituted alkyl groups and substituted or unsubstituted cycloalkyl groups;

[0052] X is selected from: H, Cl, and Br.

[0053] In some embodiments, R a Selected from: substituted or unsubstituted C 1-10 Alkyl, substituted or unsubstituted heteroalkyl containing 1-10 carbons and 1-3 heteroatoms, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted 5-10 membered heterocyclic groups, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 heteroaryl, substituted or unsubstituted C 6-10 Aryl C 1-10 Alkyl and substituted or unsubstituted 5-10 membered heteroaryl C 1-10 alkyl;

[0054] R c Each is independently selected from: substituted or unsubstituted C 1-10 Alkyl, substituted or unsubstituted C 1-10Alkoxy, substituted or unsubstituted heteroalkyl containing 1-10 carbons and 1-3 heteroatoms, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted 5-10 membered heterocyclic groups, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 heteroaryl, substituted or unsubstituted C 6-10 Aryl C 1-10 Alkyl and substituted or unsubstituted 5-10 membered heteroaryl C 1-10 alkyl;

[0055] R d Each is independently selected from: H, halogen, substituted or unsubstituted C. 1-10 Alkyl, substituted or unsubstituted C 1-10 Alkoxy, substituted or unsubstituted heteroalkyl containing 1-10 carbons and 1-3 heteroatoms, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted 5-10 membered heterocyclic groups, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 heteroaryl, substituted or unsubstituted C 6-10 Aryl C 1-10 Alkyl and substituted or unsubstituted 5-10 membered heteroaryl C 1-10 alkyl;

[0056] When R d In R c When adjacent, any location can be chosen, R d and R c Together with the atoms they are attached to, they form substituted or unsubstituted carbon atoms. 6-10 Aryl or substituted or unsubstituted 5-10 membered heteroaryl groups;

[0057] R e Selected from: substituted or unsubstituted C 1-10 Alkyl and substituted or unsubstituted C 3-10 Cycloalkyl.

[0058] In some embodiments, the molar ratio of N-acyliminoquinone (E-2) to aminoaryl (N-2) is 1:(0.6-2); the molar ratio of N-acyliminoquinone (E-3) to indole derivative (N-3) is 1:(0.6-2).

[0059] In some embodiments, the molar ratio of N-acyliminoquinone (E-2) to aminoaryl (N-2) is 1:(0.8-1.5); the molar ratio of N-acyliminoquinone (E-3) to indole derivative (N-3) is 1:(0.8-1.5).

[0060] In some embodiments, the amount of chiral phosphoric acid is 2 to 15% molar unit, with the molar amount of N-acyliminoquinone (E-2) or N-acyliminoquinone (E-3) as unit 1.

[0061] In some embodiments, the amount of chiral phosphate is 5-10% molar monomass, with the molar amount of N-acyliminoquinone (E-2) or N-acyliminoquinone (E-3) as unit 1.

[0062] In some embodiments, the solvent for the reaction is a solvent that is inert to the reaction; the temperature of the reaction is room temperature; and the reaction time is 0.5 to 5 hours.

[0063] In some embodiments, the solvent for the reaction is an aprotic organic solvent.

[0064] In some embodiments, the solvent for the reaction is one or more combinations of dichloromethane, dichloroethane, trichloromethane, toluene, and xylene.

[0065] Terminology Explanation

[0066] Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover all alternatives, modifications, and equivalents, all of which are included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many similar or equivalent methods and materials can be used to practice the invention. The invention is by no means limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ from or contradict this application (including, but not limited to, defined terminology, application of terminology, described techniques, etc.), this application shall prevail.

[0067] It should be further appreciated that certain features of the invention, for clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the invention, for brevity, have been described in a single embodiment, but may also be provided individually or in any suitable sub-combination.

[0068] Unless otherwise stated, all technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. All patents and publications related to this invention are incorporated herein by reference in their entirety.

[0069] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0070] In the following content, all figures disclosed herein, whether or not the words "approximately" or "about" are used, are approximate values. The value of each figure may vary by 1%, 2%, 5%, 7%, 8%, 10%, 15%, or 20%, etc. Whenever a figure with a value of N is disclosed, any figure with a value of N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, N+ / -10%, N+ / -15%, or N+ / -20% will be explicitly disclosed, where "+ / -" indicates addition or subtraction.

[0071] Unless otherwise expressly indicated, the descriptive terms “each…independently”, “…each…independently”, and “…independently” used in this invention are interchangeable and should be interpreted broadly. They can mean that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0072] The terms “optional,” “optionally,” or “arbitrarily” mean that the event or situation described below may, but is not necessarily, occur, and the description includes both the possibility that the event or situation occurs and the possibility that it does not occur. For example, “optionally replaced by…” means that the replacement may or may not occur.

[0073] When the terms “independent” and “arbitrarily” are used together, for example, “independently and arbitrarily replaced by…”, it means that specific options are replaced by or not replaced by each other without affecting each other.

[0074] The term "unsaturated" or "unsaturated" means that a portion contains one or more degrees of unsaturation.

[0075] When used as a prefix to a functional group, the term "substituted or unsubstituted" in this invention refers to both cases where the group is substituted by the substituents described in this invention and cases where it is not substituted by the substituents described in this invention. The substituents involved in "substituted" are conventional substituents in the art, such as, but not limited to, hydroxyl, cyano, nitro, amino, mercapto, halogen, oxo, ester, alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocyclic, etc., and these conventional substituents can be further substituted. The substituents involved in "substituted" can also be unconventional substituents in the art, which can be substituent fragments formed by a reasonable combination of conventional substituents. The common feature of these substituents is that they do not affect the process of the method described in this invention.

[0076] The term "substitution" refers to the replacement of one or more hydrogen atoms on a specific group by a specific substituent. The specific substituent is either the substituent described accordingly above or the substituent appearing in the various embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substituted site of that group, and the substituents may be the same or different at each position, i.e., the various substitutions are independent of each other. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are those that are stable or chemically feasible.

[0077] The term "heteroatom" refers to O, S, N, P, and Si, including any oxidation state of S, N, and P; primary, secondary, tertiary amines, and quaternary ammonium salts; or forms in which the hydrogen atom on the nitrogen atom in the heterocycle is substituted, for example, N (like N in 3,4-dihydro-2H-pyrrole), NH (like NH in pyrrolidinyl), or NRT (like NRT in N-substituted pyrrolidinyl, where RT is a substituent on N). In the compounds of this invention, when containing multiple heteroatoms, the resulting compounds conform to the covalent and compositional rules of organic compounds; that is, compounds containing multiple heteroatoms should exclude those that do not conform to the covalent and compositional rules of organic compounds.

[0078] The term "substituted or unsubstituted aryl" refers to an aryl group that is substituted by or not substituted by the substituents described in this invention. "Aryl" or "aromatic ring" refers to aromatic carbocyclic systems that are monocyclic, bicyclic, or tricyclic. The term "aryl" may be used interchangeably with the terms "aromatic ring" or "aromatic ring". A 6-10 membered aryl group refers to an aryl group containing 6-10 ring atoms. Examples include, but are not limited to, phenyl and naphthyl groups.

[0079] The term "substituted or unsubstituted heteroaryl" refers to a heteroaryl group that is substituted by or not substituted by the substituents described in this invention. "Hyperaryl" or "heteroaryl ring" refers to a monocyclic, bicyclic, or tricyclic aromatic system containing a heteroatom. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring" or "heteroaryl compound." The heteroatom has the definition described in this invention. In some embodiments, a heteroaryl is a heteroaryl consisting of 5-10 atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, i.e., a 5-10-membered heteroaryl; a heteroaryl is a heteroaryl consisting of 5-8 atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, i.e., a 5-8-membered heteroaryl; in some embodiments, a heteroaryl is a heteroaryl consisting of 5-7 atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, i.e., a 5-7-membered heteroaryl. In some embodiments, the heteroaryl group is a heteroaryl group consisting of 5-6 atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, i.e., a 5-6 membered heteroaryl group; in some embodiments, the heteroaryl group is a heteroaryl group consisting of 5 atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, i.e., a 5 membered heteroaryl group; in some embodiments, the heteroaryl group is a heteroaryl group consisting of 6 atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, i.e., a 6 membered heteroaryl group.

[0080] The term "substituted or unsubstituted alkyl" refers to an alkyl group that is either substituted by or not substituted by the substituents described in this invention. "alkyl" or "alkyl group" indicates a carbon-containing, saturated straight-chain or branched hydrocarbon group. In one embodiment, the alkyl group contains 1-6 carbon atoms, i.e., C64-C ... 1-6 Alkyl group; in yet another embodiment, the alkyl group contains 1-4 carbon atoms, i.e., C64-C44-C6 ... 1-4 Alkyl group; in another embodiment, the alkyl group contains 1-3 carbon atoms, i.e., C64-C ... 1-3 Alkyl groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl and similar alkyl groups.

[0081] The term "substituted or unsubstituted heteroalkyl" refers to a heteroalkyl group that includes those substituted by the substituents described in this invention or those not substituted by the substituents described in this invention. A "heteroalkyl" is a group formed by adding one or more heteroatoms to an alkyl group. The alkyl group and heteroatoms are as defined in this invention. In some embodiments, the heteroalkyl group contains 1-8 carbon atoms and 1-3 heteroatoms; in some embodiments, the heteroalkyl group contains 1-6 carbon atoms and 1-2 heteroatoms. The heteroalkyl group can be attached to the remainder of the molecule via carbon atoms or heteroatoms. In some embodiments of this invention, the heteroalkyl group is attached to the remainder of the molecule via carbon atoms.

[0082] The term "substituted unsubstituted cycloalkyl" refers to a cycloalkyl group that includes those substituted by the substituents described in this invention or those not substituted by the substituents described in this invention. "Cycloalkyl" means a monocyclic, bicyclic, or tricyclic system containing a carbon atom, either monocyclic or polycyclic (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl), or bicyclic, including spirocyclic, fused, or bridged systems (e.g., bicyclic [1.1.1]pentyl, bicyclic [2.2.1]heptyl, bicyclic [3.2.1]octyl, or bicyclic [5.2.0]nonyl, decahydronaphthyl, etc.), which may be fully saturated or contain one or more unsaturations, but may not contain any aromatic rings. In one embodiment, the cycloalkyl group contains 3-6 carbon atoms, such as C 3-6 Saturated or partially unsaturated cycloalkyl groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, etc. In one embodiment, the saturated or partially unsaturated cycloalkyl group is selected from: saturated monocyclic cycloalkyl, saturated bicyclic cycloalkyl, saturated tricyclic cycloalkyl, partially unsaturated monocyclic cycloalkyl, partially unsaturated bicyclic cycloalkyl, and partially unsaturated tricyclic cycloalkyl. C 4-7 Cycloalkyl refers to cycloalkyl groups with 4-7 ring atoms. C 3-6 Cycloalkyl refers to cycloalkyl groups with 3 to 6 ring atoms.

[0083] The term "substituted or unsubstituted heterocyclic group" refers to a heterocyclic group that includes cases where it is substituted by the substituents described in this invention or cases where it is not substituted by the substituents described in this invention. "Heterocyclic group" refers to a saturated (i.e., "heterocyclic alkyl") or partially unsaturated monovalent monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms in the ring and one or more (e.g., one, two, three, or four) heteroatom-containing groups selected from C(=O), O, S, S(=O), S(=O)2, and NR', wherein R' represents a hydrogen atom or C 1-6 Alkyl or halogenated -C 1-6 Alkyl group. The heterocyclic group may be attached to the remainder of the molecule by any one of the carbon atoms or a nitrogen atom (if present). In particular, 3-10 membered heterocyclic groups are groups having 3-10 (e.g., 3-7, 4-6, or 5-6) carbon atoms and heteroatoms in the ring, such as, but not limited to, ethylene oxide, aziridinyl, and azetidinyl.

[0084] The term "substituted or unsubstituted arylalkyl" refers to an arylalkyl group that is either substituted by or not substituted by the substituents described in this invention. "Arylalkyl" means aryl-alkyl-, wherein aryl and alkyl have the definitions described in this invention.

[0085] The term "substituted or unsubstituted heteroarylalkyl" refers to a heteroarylalkyl that includes the case of being substituted with a substituent described in the present invention or not being substituted with a substituent described in the present invention. "Heteroarylalkyl" refers to heteroaryl-alkyl-, wherein heteroaryl and alkyl have the definitions described in the present invention.

[0086] The term "hydrogen" refers to 1 H; "deuterium" refers to 2 H.

[0087] The terms "halogen" and "halo" refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0088] The term "amino" refers to -NH2.

[0089] The term "hydroxy" refers to -OH.

[0090] The term "mercapto" refers to -SH.

[0091] The term "cyano" refers to -CN.

[0092] The term "nitro" refers to -NO2.

[0093] The term "carboxy" refers to HO(C=O)-.

[0094] The term "oxo" is used interchangeably with "O=", that is, when the substituent is O=, O is connected to the substituted group via a double bond.

[0095] The term "thio" is used interchangeably with "S=", that is, when the substituent is S=, S is connected to the substituted group via a double bond.

[0096] The term "comprising" is synonymous with "including", "containing" or "characterized by", it is inclusive or open-ended, and does not exclude additional unrecited elements or ingredients from the medicament (or steps in the case of a method). The phrase "consisting of" does not include any element, step or ingredient not specified in the medicament (or steps in the case of a method). The phrase "consisting essentially of" refers to the specified materials and those materials that do not materially affect the basic and novel characteristics of the medicament (or steps in the case of a method).

[0097] As described herein, a ring system formed by a substituent R connected to a central ring through a bond (as shown in the formula below) means that the substituent R is substituted at any substitutable or any reasonable position on the ring A. For example, formula f represents any possible substitutable position on ring A, as shown in formulas f1-f4:

[0098]

[0099] As described in this paper, a ring system is formed by a substituent being linked by a single bond to a central ring, such as (R x ) n , representing n substituents R x It can be substituted at any substituted position on the ring. For example, formula a represents that the benzene ring can be substituted by n R groups. x replace.

[0100] Detailed Implementation

[0101] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. The specific embodiments described herein are for illustrative purposes only and are not intended to limit the invention in any way. Furthermore, descriptions of well-known structures and techniques are omitted in the following description to avoid unnecessarily obscuring the concepts of this disclosure. Such structures and techniques have also been described in many publications.

[0102] All reagents used in this invention can be purchased commercially or prepared by the methods described in this invention.

[0103] Preparation of raw materials and intermediates:

[0104] Option 1:

[0105]

[0106] Step 1) Add acid anhydride (5.0 mmol) to a solution of P-1 (5.0 mmol) in 30 mL of anhydrous ethanol. Stir the solution at 25 °C for 12 hours, then evaporate to dryness. Purify the residue by silica gel column chromatography (PE / CH2Cl2 = 1 / 2 to CH2Cl2 as eluent) to obtain pure product B-1.

[0107] When R 1 For H, R 2 For methyl, R 3 For phenyl:

[0108] Yield: 85%.

[0109] 1 H NMR(400MHz,DMSO-d6)δ11.36(s,1H),9.41(s,1H),7.79-7.76(m,2H),7.50-7.4 6(m,2H),7.39-7.31(m,3H),7.14-7.10(m,1H),7.02-6.98(m,1H),2.10(s,3H).

[0110] 13 C NMR (100Hz, DMSO-d6) δ169.61,134.48,131.69,131.25,128.68,127.39,126.62,126.16,121.89,119.01,118.42,111.34,110.80,22.78.

[0111] HRMS (ESI) calculated value C 16 H 13 N2O - [MH] - 249.1033; Detected value: 249.1031.

[0112] Step 2) At 0°C, PhI(OAc)2 (PIDA, 1.0 mmol) was added in a single batch to a suspension of B-1 (1.0 mmol) in CH2Cl2 (10 mL). After stirring at 0°C for 1 hour, the mixture was reacted at 25°C (approximately 2 hours). When the reaction was complete, it was quenched by adding saturated NaHCO3 (20 mL). The organic phase was separated, washed with saturated NaHCO3 (20 mL × 2) and H2O (20 mL × 2), and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product solid. The crude product solid was washed with petroleum ether (PE) or purified by silica gel column chromatography (PE / CH2Cl2 = 1 / 1 as eluent) to obtain product E-1 (the yields, NMR, and mass spectrometry data of E-1m to E-1u are shown in Table 1).

[0113] Table 1

[0114]

[0115]

[0116] Option 2:

[0117]

[0118] Step 1): At 0°C, add sulfonyl chloride (R) to a stirred solution of P-2 (10.0 mmol) in pyridine (20 mL). a SO2Cl (11.0 mmol) was added, and the reaction mixture was stirred at 25 °C for 4 hours. Water (10 mL) was added to destroy the sulfonyl chloride, and the mixture was stirred at 25 °C for 0.5 hours. The reaction mixture was concentrated under reduced pressure and then dissolved in ethyl acetate (100 mL). The organic layer was separated and washed with 1N HCl (20 mL × 5) and saturated brine (20 mL × 2). The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by silica gel column chromatography (CH2Cl2 as eluent) to give product B-2.

[0119]

[0120] Yield: 92%.

[0121] 1 H NMR (400MHz, DMSO-d6) δ10.21(s,1H),10.03(s,1H),7.62-7.60(m,2H),7.35-7.33(m,2H),7.04(s,2H),2.31(s,3H).

[0122] 13 C NMR (100MHz, DMSO-d6) δ146.21,143.60,136.05,130.52,129.85,126.76,122.61,121.07,21.00.

[0123] HRMS (ESI) calculated value C 13 H 10 Cl2NO3S - [MH] - 329.9764; Detected value: 329.9766.

[0124] Step 2) Under a N2 atmosphere, Ag2O (3.0 mmol) and magnesium sulfate (3.0 mmol) were added to a solution of B-2 (1.5 mmol) in anhydrous CH2Cl2 (15 mL). The reaction mixture was stirred at 25 °C for 2 hours (when R... a When 4-(trifluoromethyl)phenyl and 4-nitrophenyl are reacted, the reaction temperature is 50°C. After filtration, the filtrate is evaporated under vacuum to provide the desired product E-2 (the yields, NMR, and mass spectrometry data of E-2a to E-2o are shown in Table 2).

[0125] Table 2

[0126]

[0127]

[0128] Option 3:

[0129]

[0130] E-3 was prepared according to the method in Scheme 2. (The yields, NMR and mass spectrometry data of E-3a to E-3n are shown in Table 3).

[0131] Table 3

[0132]

[0133]

[0134] Option 4

[0135]

[0136] Step 1) A mixture of 6-bromo-1-tetrahydronaphthone (K-1b, 24.4 mmol, 5.49 g), methylboric acid (37.2 mmol, 2.23 g), Pd(OAc)₂ (1.24 mmol, 0.28 g), PPh₃ (2.44 mmol, 0.64 g), and K₃PO₄ (96.0 mmol, 20.8 g) with anhydrous THF (100 mL) was refluxed and stirred overnight under N₂ atmosphere. After cooling to 25 °C, the mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (PE / CH₂Cl₂ = 1 / 1 as eluent) to give 6-methyl-3,4-dihydronaphth-1(2H)-one (L-1b). Yield: 85%.

[0137] 1 H NMR (400MHz, CDCl3) δ7.93 (d, J = 8.0Hz, 1H), 7.12-7.06 (m, 2H), 2.93-2.90 (m, 2H), 2.64-2.61 (m, 2H), 2.37 (s, 3H), 2.15-2.08 (m, 2H).

[0138] 13 C NMR (100MHz, CDCl3) δ198.32,144.69,144.34,130.47,129.32,127.75,127.41,39.28,29.83,23.49,21.83.

[0139] Step 2) Under a nitrogen atmosphere, triisopropyl trifluoromethanesulfonate (6.4 mmol, 1.7 mL) was added to an anhydrous CH2Cl2 solution (15 mL) of L-1b (5.6 mmol), followed by the dropwise addition of triethylamine (TEA, 9.4 mmol, 1.3 mL) at 0 °C. The mixture was stirred at 25 °C for 2 hours and washed with cold saturated NaHCO3 aqueous solution (10 mL × 2). The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (PE as eluent) to give triisopropyl((6-methyl-3,4-dihydro-naphth-1-yl)oxy)silane.

[0140] Triisopropyl((6-methyl-3,4-dihydronaphth-1-yl)oxy)silane (5.9 mmol) and DDQ (12.0 mmol) were dissolved in anhydrous CH3CN and heated at 80 °C for 0.5 h. The mixture was cooled to 25 °C, diluted with heptane (10 mL), and then filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (PE as eluent) to give pure product M-1b. The two-step yield was 58%.

[0141] 1 H NMR (400MHz, CDCl3) δ8.17 (d, J = 8.5Hz, 1H), 7.57 (s, 1H), 7.35-7.24 (m, 3H), 6.81 (dd,J=7.5,1.1Hz,1H),2.51(s,3H),1.45-1.38(m,3H),1.17(s,9H),1.15(s,9H).

[0142] 13 C NMR (100MHz, CDCl3) δ152.20,135.83,135.42,127.40,126.74,126.11,126.04,122.75,120.09,111.34,21.78,18.27,13.22.

[0143] Step 3) At -40°C, aluminum trichloride (3.9 mmol) was added to anhydrous DCM (5 mL), followed by the dropwise addition of tBuCl (3.3 mmol). The reaction mixture was then stirred at -40°C for 10 minutes. A CH2Cl2 solution of M-1b (3.0 mmol) (2 mL) was then added dropwise, and the reaction mixture was stirred at 0°C under a N2 atmosphere for 24 hours. The reaction was quenched by adding H2O at 0°C and extracted with EtOAc (10 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was dissolved in N-methyl-2-pyrrolidone (NMP, 2 mL), followed by the addition of a solution of NaOH (1.0 g) in H2O (1 mL) and MeOH (2.8 mL), and heated at 60°C for 1.5 hours. The mixture was diluted with water (10 mL) and washed with hexane (10 mL). The aqueous layer was acidified with 6N HCl (6 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with H2O, dried over Na2SO4, and purified by silica gel column chromatography (PE / EtOAc = 25 / 1 as eluent) to give pure product N-1b. Yield: 51%.

[0144] 1H NMR (400MHz, CDCl3) δ7.99(d,J=8.5Hz,1H),7.57(s,1H),7.31-7.27(m,2H),6.85(d,J=1.7Hz,1H),5.23(s,1H),2.51(s,3H),1.38(s,9H).

[0145] 13 C NMR (100MHz, CDCl3) δ151.09,149.38,136.16,135.05,127.02,126.98,121.05,120.97,115.46,107.13,34.94,31.34,21.81.

[0146] HRMS (ESI) calculated value C 15 H 19 O + [M+H] + 215.1430; Detected value: 215.1428.

[0147] Option 5

[0148]

[0149] Aluminum trichloride (30.0 mmol) was added fractionally to an anhydrous CH2Cl2 (30 mL) solution of 1-methoxynaphthalene (10.0 mmol) and tBuCl (30 mL). The reaction mixture was stirred at 25 °C for 12 hours. The solution was carefully quenched by adding 3N HCl (50 mL) at 0 °C and extracted with CH2Cl2 (10 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated. The crude product M-1c was dissolved in CH2Cl2 (50 mL) and cooled to -78 °C. BBr3 (20.0 mmol) was added and the mixture was stirred overnight at 25 °C. The reaction was quenched by adding H2O. The organic phase was separated, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (PE / CH2Cl2 = 2 / 1 as eluent) to give product N-1c. Yield: 82%.

[0150] 1 H NMR (400MHz, CDCl3) δ8.10 (s, 1H), 7.78 (d, J = 8.0Hz, 1H), 7.62-7.59 (m, 1H) ,7.39(s,1H),6.91(d,J=1.7Hz,1H),5.63(s,1H),1.45(s,9H),1.39(s,9H).

[0151] 13C NMR (100MHz, CDCl3) δ151.06,148.58,147.63,132.91,127.64,125.41,122.49,116.10,115.56,107.93,35.08,34.84,31.45,31.32.

[0152] HRMS (ESI) calculated value [MH] - C 18 H 23 O - 255.1754; Detected value: 255.1758.

[0153] Option 6

[0154]

[0155] Step 1) Under a nitrogen atmosphere, 2'-bromoacetophenone derivative (L-1, 10.0 mmol), 3,3-dimethylbut-1-yne (20.0 mmol, 1.64 g), and anhydrous Et3N (30 mL) were placed into a dry 100 mL three-necked round-bottom flask. Then, under a nitrogen atmosphere, Pd(PPh3)2Cl2 (0.5 mmol) and CuI (0.5 mmol) were added to the flask. The mixture was stirred at 80 °C for 12 hours until L-1 was consumed (monitored by TLC). The reaction mixture was diluted with ethyl acetate (100 mL) and washed with 3N HCl (30 mL x 3) and H2O (30 mL x 3). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / CH2Cl2 = 1 / 2 as eluent) to give product M-1.

[0156] Step 2) Under a nitrogen atmosphere and at 25°C, a solution of 10.0 mmol of o-tert-butylethynylacetone derivative M-1 in anhydrous THF (10 mL) was added in a single batch to a mixture of 1.0 M, 30.0 mmol of anhydrous THF in tBuOK. The reaction mixture was heated at 80°C for 24 hours and then cooled to 25°C. The reaction mixture was acidified at 0°C with 1.0 M H2SO4 (30 mL) for 2 hours and then extracted with EtOAc (30 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / CH2Cl2 = 1 / 1 as eluent) to give product N-1.

[0157] N-1d and N-1e were synthesized using this method, and the yield, NMR, and mass spectrometry data are shown in Table 4.

[0158] Table 4

[0159]

[0160] Option 7

[0161]

[0162] Step 1) CuI (24.0 mmol, 4.56 g) and KOMe (60.0 mmol, 4.21 g) were added to an anhydrous MeOH (50 mL) solution of 1,8-dibromonaphthalene (K-1f, 20.0 mmol, 5.70 g). The mixture was stirred at 80 °C for 12 hours, cooled to 25 °C, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE as eluent) to give 1-bromo-8-methoxy-naphthalene (L-1f). Yield: 46%.

[0163] 1 H NMR (400MHz, CDCl3) δ7.78 (dd, J=7.5, 1.2Hz, 1H), 7.74 (dd, J=8.2, 1.2Hz, 1H), 7.45-7.38(m,2H),7.24-7.21(m,1H),6.92(dd,J=7.3,1.6Hz,1H),3.97(s,3H).

[0164] 13 C NMR (100MHz, CDCl3) δ155.83,137.11,132.99,128.06,126.62,126.46,123.82,121.47,116.70,107.21,55.75.

[0165] Step 2) A mixture of 8-bromo-1-methoxynaphthalene (L-1f, 9.3 mmol, 2.2 g), methylboric acid (14.2 mmol, 0.92 g), Pd(OAc)₂ (0.47 mmol, 0.11 g), PPh₃ (0.93 mmol, 0.24 g), and K₃PO₄ (36.0 mmol, 7.8 g) in anhydrous THF (45 mL) was refluxed and stirred overnight under N₂ atmosphere. After cooling to 25 °C, the reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated. The residue was purified by silica gel column chromatography (PE as eluent) to give 1-methyl-8-methoxynaphthalene (M-1f). Yield: 93%.

[0166] 1H NMR (400MHz, CDCl3) δ7.67-7.64(m,1H),7.44(dd,J=8.2,1.3Hz,1H),7.39-7.33( m,2H),7.24-7.22(m,1H),6.83(dd,J=7.5,1.2Hz,1H),3.95(s,3H),2.94(s,3H).

[0167] 13 C NMR (100MHz, CDCl3) δ158.24,136.30,135.45,128.43,126.30,126.02,125.61,125.37,121.39,105.28,55.39,25.33.

[0168] Step 3) At -40°C, an anhydrous CH2Cl2 solution of aluminum trichloride (3.9 mmol) in 5 mL was added dropwise to tBuCl (3.3 mmol), and the reaction mixture was stirred at -40°C for 10 minutes. Then, a CH2Cl2 solution of 1-methyl-8-methoxy-naphthalene (M-1f, 3.0 mmol) in 2 mL was added dropwise, and the reaction mixture was stirred at 0°C under a N2 atmosphere for 24 hours. The reaction was quenched by adding H2O at 0°C, and extracted with EtOAc (10 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated by rotary evaporation. The crude product was dissolved in CH2Cl2 (5 mL) and cooled to -78°C. BBr3 (6.0 mmol) was added, and the mixture was stirred overnight at 25°C. The reaction was quenched by adding H2O. The organic phase was separated, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (PE / CH2Cl2 = 1 / 1 as eluent) to give the product 3,7-di-tert-butyl-8-methylnaphthalene-1-ol (N-1f). Yield: 51%.

[0169] 1 H NMR (400MHz, CDCl3) δ7.54(d,J=2.1Hz,1H),7.34(d,J=1.8Hz,1H),7.22-7.21(m ,1H),6.75(d,J=1.9Hz,1H),5.16(s,1H),2.95(s,3H),1.40(s,9H),1.38(s,9H).

[0170] 13C NMR (100MHz, CDCl3) δ153.37,148.76,148.56,136.57,133.96,126.48,121.55,120.38,117.05,108.70,34.63,34.61,31.27,31.24,24.71.

[0171] HRMS (ESI) calculated value C 19 H 27 O + [M+H] + 271.2056; Detected value: 271.2056.

[0172] Option 8:

[0173]

[0174] Step 1) Under a nitrogen atmosphere at 0°C, MeMgBr (24.0 mmol) was added dropwise to an anhydrous THF (20 mL) solution of 2-bromobenzaldehyde derivative K-2 (20.0 mmol) and stirred at 0°C. After completion, the reaction was quenched with saturated NH4Cl solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography to give product 1. A mixture of PCC (45.0 mmol) and silica gel (PCC / silica gel = 1 / 1 (w / w)) was added to a solution of product 1 (15.0 mmol) in CH2Cl2 (50 mL). The reaction mixture was stirred at 25°C for 1 hour. After completion, the reaction mixture was filtered through a silica gel stencil containing CH2Cl2 as the eluent. The resulting solution was concentrated and the residue was purified by silica gel column chromatography (PE / CH2Cl2 = 4 / 1 as the eluent) to give product L-2.

[0175] Step 2) Under a nitrogen atmosphere, 10.0 mmol of 2'-bromoacetophenone derivative L-2, substituted alkyne (20.0 mmol), and anhydrous Et3N (30 mL) were placed into a dry 100 mL three-necked round-bottom flask. Then, under a nitrogen atmosphere, 0.5 mmol of Pd(PPh3)2Cl2 and 0.5 mmol of CuI were added to the flask. The mixture was stirred at 80 °C for 12 hours until L-2 was completely consumed (TLC monitoring). The reaction mixture was diluted with 100 mL of ethyl acetate and washed with 3N HCl (30 mL x 3) and H2O (30 mL x 3). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on a silica gel column (PE / CH2Cl2 = 2 / 1 as eluent) to give product M-2.

[0176] Step 3) A mixture of M-2 (10.0 mmol), aniline derivative (20.0 mmol), Cu(OAc)2·H2O (2.0 mmol), and 30 mL of degassed toluene was heated at 110 °C under a N2 atmosphere. When the TLC showed that the reaction was complete (approximately 24 hours), the solvent was evaporated, and the residue was purified by silica gel column chromatography (PE / CH2Cl2 = 2 / 1 as eluent) to obtain product N-2. (The yields, NMR, and mass spectrometry data of N-2h to N-2u are shown in Table 5).

[0177] Table 5

[0178]

[0179]

[0180] Option 9

[0181]

[0182] Step 1) Compound K-3 (5.0 mmol, 1.11 g) was dissolved in anhydrous THF (30 mL) under a nitrogen atmosphere. Me₂Zn (15.0 mmol, 1.0 M in toluene) was added dropwise using a syringe under a nitrogen atmosphere. After the addition was complete, Pd(dppf)Cl₂ (5.0 mol%) was added in portions. The mixture was heated at 80 °C for 24 hours. The reaction mixture was cooled to 25 °C and carefully quenched with H₂O (5 mL). The mixture was extracted with EtOAc (10 mL × 3), and the combined organic layers were dried over Na₂SO₄. After evaporation of the solvent, the residue was purified by silica gel column chromatography (PE / CH₂Cl₂ = 1 / 1 as eluent) to give product L-3.

[0183] Step 2) At 0°C, RCOCl (10.0 mmol) was added dropwise to a CH2Cl2 (50 mL) solution of L-3 (10.0 mmol, 1.57 g) and Et3N (15.0 mmol). The reaction mixture was stirred at 25°C for 4 hours, then washed with 2N HCl (30 mL × 3) and H2O (30 L mL × 2), and dried over Na2SO4. After evaporating the solvent, the residue was purified by recrystallization from petroleum ether (PE) to give product M-3.

[0184] Step 3) Under a nitrogen atmosphere and at 0°C, nBuLi (24.0 mmol) was added dropwise to M-3 (10.0 mmol) in anhydrous THF (30 mL). The reaction mixture was stirred at 25°C for 12 hours. The reaction mixture was carefully quenched with H2O (5 mL). The mixture was extracted with EtOAc (20 mL × 3) and dried over Na2SO4. After evaporation of the solvent, the residue was purified by silica gel column chromatography (PE / CH2Cl2 = 4 / 1 as eluent) to give product N-3.

[0185] Option 10

[0186]

[0187] Step 1) A solution of sodium nitrite (128.0 mmol) in H₂O (25 mL) was added dropwise to a concentrated solution of 2-naphthylamine derivative L-3' (100.0 mmol). HCl (120 mL) was added at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. Then, a concentrated solution of stannous chloride dihydrate (350.0 mmol) was added dropwise to the above mixture at 0 °C. The resulting reaction mixture was stirred at 0 °C for 3.5 hours. The mixture was filtered and the filter cake was washed with ice water and Et₂O / hexane (1 / 1). After drying, the desired product M-3' was obtained.

[0188] Step 2) Conclusion. At 25°C, 25 mL of H₂SO₄ was added dropwise to a mixture of hydrazine hydrochloride M-3 (50.0 mmol), pinacolone (50 mL), and H₂O (10 mL). The reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was then cooled to 25°C and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with saturated NaHCO₃ aqueous solution (30 mL × 3) and saturated brine (30 mL × 2), and dried over Na₂SO₄. After solvent evaporation, the residue was purified by silica gel column chromatography (PE / CH₂Cl₂ = 20 / 1 to PE / CH₂Cl₂ = 8 / 1 as eluent) to give pure product N-3.

[0189] (The yield, NMR, and mass spectrometry data of N-3c to N-2u are shown in Table 6).

[0190] Table 6

[0191]

[0192]

[0193] I. Formation of chiral CN bonds

[0194] Preparation Example 1-1: Synthesis of chiral amine product 42

[0195]

[0196] In a dry Schlenk tube, compound E-1m (0.1 mmol), compound N-1c (0.15 mmol), and 10 mol% chiral phosphoric acid (CPA) were stirred at -40 °C for 5 minutes. Then, the solvent was added in one go through a syringe, and the mixture was reacted at -40 °C to room temperature for 5–20 minutes to obtain chiral amine product 42.

[0197] HPLC conditions: Chiralpak IF (n-hexane / i-PrOH = 85 / 15, 1.0 mL / min, t R (major) = 6.2 min, t R (minor) = 6.9min).

[0198] 1 H NMR (400MHz, CDCl3) δ9.65 (s, 1H), 7.75 (d, J = 8.0Hz, 1H), 7.50-7.45 (m, 3H), 7.39-7.37 (m, 3H), 7.23 (d, J = 8.1Hz, 1H), 7.14-7.12 (m,2H),6.98(t,J=7.2Hz,1H),6.62(t,J=7.4Hz,1H),6.19(d,J=8.0Hz,1H),5.83(s,1H),2.15(s,3H),1.16(s,9H),0.88(s,9H).

[0199] 13 C NMR (100MHz, CDCl3) δ186.21,173.70,165.23,151.72,138.44,137.27,134.03,133.90,132.59,129.21,129.09,129.02,12 8.87,128.54,128.34,127.52,121.97,121.58,120.49,117.38,111.54,109.31,50.88,37.07,34.74,31.30,28.16,24.15.

[0200] HRMS (ESI) calculated value C 34 H 37 N2O2 + [M+H] + 505.2850; Detected value: 505.2843.

[0201] The structures of (R)-C1 to (R)-C5 are as follows:

[0202]

[0203] The reaction conditions and results for different CPA, solvents, reaction temperatures, and reaction times are shown in Table 7.

[0204] Table 7

[0205] 1 (R)-C1 <![CDATA[CH2Cl2]]> r.t. 5 98 0 2 (R)-C2 <![CDATA[CH2Cl2]]> r.t. 5 97 44 3 (R)-C3 <![CDATA[CH2Cl2]]> r.t. 5 98 18 4 (R)-C4 <![CDATA[CH2Cl2]]> r.t. 5 94 74 5 (R)-C5 <![CDATA[CH2Cl2]]> r.t. 5 98 77 6 (R)-C5 <![CDATA[CHCl3]]> r.t. 5 96 79 7 (R)-C5 dichloroethane r.t. 5 97 82 8 (R)-C5 Toluene r.t. 5 97 84 9 (R)-C5 Toluene 0℃ 10 97 86 10 (R)-C5 Toluene -40℃ 20 97 91

[0206] The above study reveals that the structure of the catalyst used in this type of reaction has a significant impact on the chiral ee value. When (R)-C1 is used as the catalyst, the reaction is rapid, completing within 5 minutes to obtain a high yield, but the ee value is 0. When other aryl side chains at the 3,3'- positions are selected, ideal results are obtained. In particular, (R)-C5 provides the best stereoselectivity control environment, yielding the chiral amine product 42 with the highest ee value.

[0207] Preparation Examples 1-2: Synthesis of chiral amine products 43-54

[0208]

[0209] In a dry Schlenk tube under a nitrogen atmosphere, compounds E-1 (0.2 mmol), N-1 (0.3 mmol), and 10 mol% (R)-C5 were dispersed and dissolved in anhydrous toluene and reacted at -40 °C for 20–30 minutes to obtain chiral amine products 43–54. The specific product structures and results are shown in Table 8.

[0210] Table 8

[0211]

[0212]

[0213]

[0214] tBu is tert-butyl, Ph is phenyl, Cy is cyclohexyl, iPr is isopropyl, n-Hexyl is n-hexane, nPr is n-propyl, Me is methyl, and MeO is methoxy.

[0215] When 1-naphthol has alkyl or halogen substituents, it can also react with E-1 within 30 minutes to generate chiral amines 43-46, with high yields of 86-90% and satisfactory enantioselectivity of 81-95% ee. When the acetyl group of E-1m in Preparation Example 1-1 is replaced with other alkyl acyl groups, the results for chiral amines 47-51 show that the reaction described in this invention has high tolerance to different N-acyl components, with reaction yields reaching 90-92% and stereoselectivity of 90-93% ee, unaffected by other alkyl acyl groups besides acetyl. Similarly, chiral amines 52-54 corresponding to N-aramid imides also yield satisfactory yields of 75-82% and stereoselectivity of 80-83% ee.

[0216] II. Formation of CN-axis chiral aryl skeleton

[0217] Preparation Example 2-1: Synthesis of CN-axis chiral aryl compound 55

[0218]

[0219] In a dry Schlenk tube under a nitrogen atmosphere, compounds E-2a (0.1 mmol), N-2i (0.1 mmol), and chiral phosphoric acid (CPA, 5 mol%) were dispersed in anhydrous toluene and reacted at 25 °C for 4 hours. After the reaction was complete, the solvent was removed from the reaction solution under reduced pressure, and the residue was purified by silica gel column chromatography (CH2Cl2 / PE = 2 / 1 as eluent) to give CN-axis chiral aryl compound 55.

[0220] HPLC conditions: Chiralpak ID (n-hexane / i-PrOH (0.1% TFA) = 90 / 10, 1.0 mL / min, t R (major) = 15.0 min, t R (minor) = 20.0 min).

[0221] 1 H NMR (400MHz, CDCl3) δ7.93 (d, J = 8.3Hz, 1H), 7.57-7.53 (m, 3H), 7.41 (s, 2H), 7.33-7.29 (m, 1H), 7.20-7.11 (m, 6 H), 6.87-6.83 (m, 1H), 6.72 (d, J = 8.6Hz, 1H), 6.08 (s, 1H), 5.59 (s, 1H), 2.41 (s, 3H), 2.37 (s, 3H), 1.48 (s, 9H).

[0222] 13C NMR (100MHz, CDCl3) δ150.28,144.62,143.49,140.53,140.20,137.14,136.49,132.69,131.80,130.22,129.47 ,128.94,126.09,126.06,125.29,123.62,121.33,120.93,119.95,118.83,113.95,37.92,32.48,21.71,20.93.

[0223] HRMS (ESI) calculated value: C 34 H 33 Cl2N2O3S + [M+H] + 619.1583; Detected value: 619.1583.

[0224] The reaction conditions and results for different CPAs are shown in Table 9.

[0225] Table 9

[0226]

[0227] As shown above, the 3,3'-side arm of CPA has a significant impact on reaction efficiency and stereoselectivity. When the amount of CPA catalyst is increased, such as from 5 mol% to 7.5 mol%, the reaction yield and ee value are improved to some extent.

[0228] Preparation Example 2-2: Synthesis of CN-axis chiral aryl compounds 56-82

[0229]

[0230] In a dry Schlenk tube under a nitrogen atmosphere, compounds E-2 (0.1 mmol), N-2 (0.1 mmol), and (R)-C10 (7.5 mol%) were dispersed in anhydrous toluene and reacted at 25 °C for 4 hours to obtain CN-axis chiral aryl compounds 56-82. The structures and results of different CN-axis chiral aryl compounds are shown in Table 10.

[0231] Table 10

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240] Wherein, tAmyl is tert-amyl and tBu is tert-butyl.

[0241] The above studies show that amine substituent modification on 1-naphthylamine does not affect the formation of the N-aryl axis at the C4 position, and the products (55-62) exhibit high selectivity (88-94% ee) and good to excellent yields (67-97%). When the halogen at E-2 is bromine, the enantiomer product 63 also has an ideal ee value. The presence of substituents on the N-2 naphthalene core has some impact on the results, but results with certain ee values ​​can still be obtained. Substitution on the sulfonyl group, such as in compounds 70-82, does not affect the product yield despite significant structural changes.

[0242] When the amino substituent -NHR of the starting material N-2 in this preparation example is replaced with a hydroxyl group, an axially chiral amide product is not obtained; instead, a dearomatized product is given. HRMS (ESI) calculated value: C 31 H 34 Cl2NO4S + [M+H] + 586.1580; Detected value: 586.1582. See below:

[0243]

[0244] Preparation Example 2-3: Synthesis of CN-axis chiral aryl compounds 86-114

[0245]

[0246] Compounds E-3 (0.25 mmol), N-3 (0.2 mmol), and (R)-C12 (5 mol%) were dispersed and dissolved in dichloroethane (DCE) in a dry Schlenk tube under a nitrogen atmosphere and reacted at 25 °C for 0.5 h. The mixture was purified by preparative TLC (CH2Cl2 as eluent) to give CN-axis chiral aryl compounds 86-114.

[0247] (R)-C12 has the following structure:

[0248]

[0249] The structures and results of different CN-axis chiral aryl compounds 86-114 are shown in Table 11.

[0250] Table 11

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258] Wherein, tAmyl is tert-amyl; 1-Adamantyl is 1-adamantyl.

[0259] Compared to benzene derivatives, the typically quinary pyrroles destabilize the linked CN axis, thus hindering chiral control in the associated transmutation. This problem is adequately addressed by imposing steric hindrance at the C4 position of indole. Stereogenic CN axes are generated in good yields (86-98, 80-90%) and enantiotropic control (mostly >90% ee) for various N-sulfonyl imides. The reaction efficiency and transmutation resistance are found to be unaffected by substituent modifications on iminoquinone (99) and indole (100-114). Similarly, tert-amyl substitution and 1-adamantyl substitution can maintain axial rigidity (100-101). Substitution of the methyl group at the C4 position can also stabilize the chiral CN axis (102). The formation of these axially chiral heteroarylsulfonamides is completed within 30 minutes.

[0260] III. Applications of chiral amine compounds

[0261] Antitumor activity of axially chiral 3-aminoindole

[0262]

[0263] A (99%, 98%ee) B (93%, 96%ee) C (61%, 89%ee)

[0264] Compounds A, B, and C exhibited significant cytotoxicity at a concentration of 50 μM. All three compounds contain free or protected indolephenol units, indicating that the oxygen atom in phenol plays a crucial role in antitumor activity. Comparative experiments with irinotecan and 5-fluorouracil, two commonly used drugs in cancer treatment, revealed that compounds A, B, and C exhibited lower IC50 values ​​under the same conditions.50 (Half-inhibitory concentration) value. Compound A, IC50 50 16.92 μM; Compound B, IC 50 23.00 μM; Compound C, IC 50 18.36 μM; Irinotecan, IC 50 93.27 μM, 5-fluorouracil, IC50 50 >100μM.

[0265] Compounds A, B, and C can be chiralized using the methods described in this invention, for example, the chiral host structure of the molecule can be constructed using the specific methods described in Preparation Examples 2-3.

[0266]

[0267] R X It can be OAc, OTf, or OH;

[0268] R Y For NHTs.

[0269] Step a: Performed using the method described in this invention.

[0270] Step b: This can be carried out using conventional methods for hydroxyl transamination in the field.

[0271] The method of this invention has been described through preferred embodiments. Those skilled in the art will readily be able to modify or appropriately alter and combine the methods and applications described herein within the scope, spirit, and context of this invention to implement and apply the technology of this invention. Those skilled in the art can refer to the content herein to appropriately improve process parameters. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the scope of this invention.

Claims

1. An organocatalytic method for forming a CN-axis-containing chiral heteroaryl skeleton compound, comprising reacting N-acyliminoquinone (E-3) and an indole derivative (N-3) in a solvent under chiral phosphoric acid catalysis to form a CN-axis-containing chiral heteroaryl skeleton compound; ； The chiral phosphoric acid is ( R -C12 has the following structure: ； The solvent for the reaction is one or more combinations of dichloromethane, dichloroethane, trichloromethane, toluene, and xylene; The reaction was carried out at room temperature. X is selected from: Cl and Br; R a Selected from: Unreplaced C 1-10 alkyl R c Selected from: Unreplaced C 1-10 alkyl; R d Selected from: H, halogens, or unsubstituted C 1-10 alkyl; R e Selected from: Unreplaced C 1-10 alkyl.

2. The method according to claim 1, characterized in that, The molar ratio of N-acyliminoquinone (E-3) to indole derivative (N-3) is 1:(0.6~2).

3. The method according to claim 1, characterized in that, The molar ratio of N-acyliminoquinone (E-3) to indole derivative (N-3) is 1:(0.8~1.5).

4. The method according to claim 1, characterized in that, The amount of chiral phosphoric acid is 2 to 15% molar monomass, with the molar amount of N-acyliminoquinone (E-3) as 1.

5. The method according to claim 1, characterized in that, The amount of chiral phosphoric acid is 5-10% molar monomass, with the molar amount of N-acyliminoquinone (E-3) as 1.

6. The method according to claim 1, characterized in that, The reaction time is 0.5 to 5 hours.

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