Novel naphthoquinone intermediates and preparation methods, chiral naphthalene compounds and preparation methods

Abstract

This application belongs to the field of organic synthesis technology, and particularly relates to a novel naphthoquinone intermediate and its preparation method, as well as a chiral naphthalene compound and its preparation method. Among them, a chiral phosphoric acid catalyst is used to dehydrate compound A to obtain a novel naphthoquinone intermediate; the general structural formula of compound A is The general structural formula of the novel naphthoquinone intermediate is Among them, R 1' , R 2' are each independently selected from one of hydrogen, alkyl, and ether, X is O or NR 3' , R 3' is one of hydrogen and acyl. A chiral phosphoric acid catalyst is used to dehydrate compound A. During the reaction, the chiral phosphoric acid catalyst acts as a Brønsted acid to dehydrate the substrate compound A, in-situ generating a novel naphthoquinone intermediate based on the naphthalene ring. This novel naphthoquinone intermediate has excellent electrophilic properties and can participate in asymmetric organic catalytic reactions as an electrophilic reagent. It expands the naphthoquinone intermediate and improves the application of the naphthoquinone intermediate in asymmetric addition reactions.

Description

Technical Field

[0001] This application belongs to the technical field of organic synthesis, and particularly relates to a novel naphthoquinone intermediate and its preparation method, as well as a chiral naphthalene compound and its preparation method. Background Art

[0002] Naphthylmethylenequinone compounds are a class of highly reactive methylenequinone intermediates based on the naphthalene ring and have received extensive attention in organic chemistry, medicinal chemistry, and biology. According to the positions of the carbonyl and methylene groups, naphthylmethylenequinones can be divided into different types. Generally speaking, the common naphthylmethylenequinones are mainly o-naphthylmethylenequinones with the methylene and carbonyl groups in the ortho position and p-naphthylmethylenequinones with the methylene and carbonyl groups in the para position. Since the methylene and carbonyl groups of these naphthylmethylenequinones often only appear in one benzene ring at the same time, in fact, these intermediates can usually be regarded as substrate derivatives of methylenequinones based on the benzene ring. Therefore, generally speaking, the reactions applicable to benzene ring methylenequinones are also applicable to them. For example, asymmetric conjugate addition, Diels - Alder reaction, and heterocyclic addition, and these reactions have also been very maturely developed and studied.

[0003] However, when the methylene and carbonyl groups are in two different benzene rings, there is relatively little research, and there are few reactions based on these novel unconventional naphthoquinones. And it is extremely difficult to achieve an asymmetric conjugate addition reaction using them. Summary of the Invention

[0004] The purpose of this application is to provide a novel naphthoquinone intermediate and its preparation method, as well as a chiral naphthalene compound and its preparation method, aiming to expand naphthoquinone intermediates to a certain extent and improve the application of naphthoquinone intermediates in asymmetric addition reactions.

[0005] To achieve the above application purpose, the technical solution adopted in this application is as follows:

[0006] In the first aspect, this application provides a preparation method of a novel naphthoquinone intermediate, including the following steps:

[0007] Dehydrating compound A using a chiral phosphoric acid catalyst to obtain a novel naphthoquinone intermediate; the general structural formula of compound A is The general structural formula of the novel naphthoquinone intermediate is Wherein, R 1' , R 2' are each independently selected from one of hydrogen, alkyl, and ether, X is O or NR 3' , and R 3' is one of hydrogen and acyl.

[0008] The preparation method of the novel naphthoquinone intermediate provided by the first aspect of the present application dehydrates compound A by using a chiral phosphoric acid catalyst. During the reaction, the chiral phosphoric acid catalyst acts as a Bronsted acid to dehydrate the substrate compound A, and in-situ generates a novel naphthoquinone intermediate based on the naphthalene ring. This novel naphthoquinone intermediate has excellent electrophilic properties and can participate in asymmetric organic catalytic reactions as an electrophilic reagent. It expands the naphthoquinone intermediate and improves the application of the naphthoquinone intermediate in asymmetric addition reactions.

[0009] In the second aspect, the present application provides a novel naphthoquinone intermediate prepared by the above method. The general structural formula of the novel naphthoquinone intermediate is wherein, R 1' , R 2' are each independently selected from one of hydrogen, alkyl, and ether, X is O or NR 3' , R 3' is one of hydrogen and acyl.

[0010] The novel naphthoquinone intermediate of the present application is prepared by the above method. The prepared novel naphthoquinone intermediate has excellent electrophilic properties and can participate in asymmetric organic catalytic reactions as an electrophilic reagent. It expands the naphthoquinone intermediate and improves the application of the naphthoquinone intermediate in asymmetric addition reactions.

[0011] In the third aspect, the present application provides a preparation method of a chiral naphthalene compound, including the following steps:

[0012] Dissolve compound A, a chiral phosphoric acid catalyst, and a nucleophile in a second organic solvent for mixing reaction. After in-situ generating a novel naphthoquinone intermediate, perform nucleophilic substitution to obtain a chiral naphthalene compound; the general structural formula of compound A is The general structural formula of the chiral naphthalene compound is wherein, R 1' , R 2' are each independently selected from one of hydrogen, alkyl, and ether, X is O or NR 3' , R 3' is one of hydrogen and acyl, and R 4' is a nucleophilic group.

[0013] The preparation method of the chiral naphthalene compound of the present application involves mixing and reacting compound A, a chiral phosphoric acid catalyst, and a nucleophile after dissolving them in an organic solvent. During the mixing reaction, first, the chiral phosphoric acid catalyst acts as a Bronsted acid to dehydrate the substrate compound A in situ to generate a novel naphthoquinone intermediate based on the naphthalene ring. This intermediate has strong electrophilic properties and high energy, making it difficult to exist stably and easy to be attacked by the nucleophile. In the reaction system, the nucleophile attacks the novel naphthoquinone intermediate. At this time, the chiral phosphoric acid catalyst acts as a Lewis base to assist in enhancing the nucleophilicity of the nucleophile. At the same time, due to the presence of large steric hindrance groups on both sides, the attack direction of the nucleophile is restricted, thereby controlling the stereoselectivity of the product. After the novel naphthoquinone intermediate is subjected to nucleophilic substitution, a chiral naphthalene compound is obtained. The present application uses the in-situ generated novel naphthoquinone intermediate electrophile based on the naphthalene ring and the nucleophile to synthesize the chiral naphthalene compound in one step, which has important application value. Moreover, this reaction undergoes the reaction mechanism of methylenequinone, which has important guiding significance for subsequent reactions of the same type.

[0014] Fourthly, the present application provides a chiral naphthalene compound prepared by the above method. The general structural formula of the chiral naphthalene compound is wherein, R 1' , R 2' are each independently selected from one of hydrogen, alkyl, and ether, X is O or NR 3' , R 3' is one of hydrogen and acyl, and R 4' is a nucleophilic group.

[0015] The chiral naphthalene compound of the present application is prepared by the above method. Using the in-situ generated novel naphthoquinone intermediate electrophile based on the naphthalene ring and the nucleophile to synthesize the chiral naphthalene compound in one step, which has important application value. Moreover, the reaction mechanism of methylenequinone has important guiding significance for subsequent reactions of the same type. Detailed implementation manners

[0016] In order to make the technical problems to be solved, technical solutions, and beneficial effects of the present application clearer, the following further elaborates on the present application in combination with examples. It should be understood that the specific examples described herein are only used to explain the present application and are not used to limit the present application.

[0017] In the present application, the term "and / or" describes the association relationship of associated objects and indicates that three relationships may exist. For example, A and / or B may represent: A exists alone, A and B exist simultaneously, and B exists alone. Wherein A and B may be singular or plural. The character " / " generally represents an "or" relationship between the associated objects before and after.

[0018] In this application, "at least one" means one or more, and "a plurality" means two or more. "At least one of the following" or similar expressions refer to any combination of these items, including any combination of single items or plural items. For example, "at least one of a, b, or c", or "at least one of a, b, and c" can both represent: a, b, c, a - b (i.e., a and b), a - c, b - c, or a - b - c, where a, b, and c can be single or multiple respectively.

[0019] It should be understood that in various embodiments of this application, the magnitudes of the sequence numbers of the above processes do not imply the order of execution. Some or all of the steps can be executed in parallel or sequentially. The execution order of each process should be determined based on its function and internal logic, and should not constitute any limitation to the implementation process of the embodiments of this application.

[0020] The terms used in the embodiments of this application are only for the purpose of describing specific embodiments, and are not intended to limit this application. The singular forms "a" and "the" used in the embodiments of this application and the appended claims are also intended to include the plural forms, unless the context clearly indicates otherwise.

[0021] The weights of the relevant components mentioned in the embodiments of the specification of this application can not only refer to the specific contents of each component, but also represent the proportional relationship of the weights between the components. Therefore, as long as the contents of the relevant components in the embodiments of the specification of this application are scaled up or down proportionally, they are within the scope disclosed in the embodiments of the specification of this application. Specifically, the mass in the embodiments of the specification of this application can be mass units well-known in the chemical industry such as μg, mg, g, kg, etc.

[0022] The terms "first" and "second" are only used for descriptive purposes to distinguish objects such as substances from each other, and cannot be understood as indicating or implying relative importance or implicitly specifying the quantity of the indicated technical features. For example, without departing from the scope of the embodiments of this application, the first XX can also be referred to as the second XX, and similarly, the second XX can also be referred to as the first XX. Thus, the features defined with "first" and "second" can explicitly or implicitly include one or more of such features.

[0023] Due to many limitations in terms of reaction activity and stereochemical control, there are significant difficulties in achieving the enantioselective reaction of naphthylmethylenequinone or azoquinone based on chiral Brønsted acid catalysis, which are specifically manifested in the following aspects:

[0024] First, common methylenequinone intermediates are usually limited to phenyl compounds. Even for methylenequinones based on naphthalene rings, the methylene group and the carbonyl group often reside within the same benzene ring, and methylenequinones dispersed in two benzene rings are extremely rare;

[0025] Second, different from the reaction with methylene quinone, the reactions involving methylene iminoquinone often require more stringent conditions. Therefore, it is very difficult to find a catalytic system that can achieve high enantioselective reactions of methylene iminoquinone.

[0026] Third, for the selection of catalyst type, in order to make the reaction have good enantioselectivity, it is a great challenge to screen a suitable chiral phosphoric acid catalyst to achieve high enantioselective control of this reaction.

[0027] Fourth, for this novel methylene quinone intermediate, since the reaction is a 1,6-addition reaction with a relatively long distance, it is a great challenge to achieve high enantioselective control of this reaction.

[0028] Fifth, when indole or carbazole is used as the nucleophile, by-products will also appear after nucleophilic attack at other sites during the reaction. Therefore, it is also a great challenge to achieve excellent chemoselectivity of the reaction through the optimization of reaction conditions.

[0029] Sixth, for the research and understanding of the reaction mechanism, it is also necessary to prove that naphthoquinone intermediates are indeed generated during the reaction process.

[0030] Based on the above considerations, in order to solve the above problems, through in-depth research, a novel naphthoquinone intermediate and its preparation method, as well as a chiral naphthalene compound and its preparation method are provided. The aim is to expand naphthoquinone intermediates and improve the application of naphthoquinone intermediates in asymmetric addition reactions.

[0031] In a first aspect, an embodiment of the present application provides a preparation method of a novel naphthoquinone intermediate, including the following steps:

[0032] S10. Dehydrating compound A with a chiral phosphoric acid catalyst to obtain a novel naphthoquinone intermediate; the general structural formula of compound A is The general structural formula of the novel naphthoquinone intermediate is Wherein, R 1' , R 2' are each independently selected from one of hydrogen, alkyl, and ether, X is O or NR 3' , and R 3' is one of hydrogen and acyl.

[0033] The preparation method of the novel naphthoquinone intermediate provided in the first aspect of the embodiment of the present application dehydrates compound A with a chiral phosphoric acid catalyst. During the reaction process, the chiral phosphoric acid catalyst acts as a Bronsted acid to dehydrate the substrate compound A, in-situ generating a novel naphthoquinone intermediate based on the naphthalene ring. This novel naphthoquinone intermediate has excellent electrophilic properties and can participate in asymmetric organocatalytic reactions as an electrophilic reagent. It expands naphthoquinone intermediates and improves the application of naphthoquinone intermediates in asymmetric addition reactions.

[0034] In some possible implementation manners, compound A is selected from 8-(hydroxy(aryl)methyl)naphthalen-2-ol of formula 1, (7-aminonaphthalen-1-yl)(aryl)methanol of formula 2; wherein, R 1 , R 2 , R 8 , R 9 are each independently selected from one of hydrogen, alkyl, and ether, and R 7 is selected from one of acyl groups. In some specific embodiments, R 1 is one of hydrogen, alkyl, and ether. More specifically, the alkyl substituent includes but is not limited to methyl, and the ether includes but is not limited to methoxy group. R 2 is one of hydrogen, alkyl, and ether. The alkyl substituent includes but is not limited to methyl, and the ether includes but is not limited to methoxy group and methylthio group. R 7 is one of acyl groups. More specifically, the acyl substituent is 1-adamantylcarbonyl. R 8 is one of hydrogen, alkyl, and ether. More specifically, the alkyl substituent includes but is not limited to methyl, and the ether includes but is not limited to methoxy group. R 9 is one of hydrogen, alkyl, and ether. The alkyl substituent includes but is not limited to methyl, and the ether includes but is not limited to methoxy group and methylthio group.

[0035] In some specific embodiments, when compound A is selected from 8-(hydroxy(aryl)methyl)naphthalen-2-ol of formula 1, it dehydrates in situ under the catalysis of a chiral phosphoric acid catalyst to generate 8-methylenenaphthalen-2-one When compound A is selected from (7-aminonaphthalen-1-yl)(aryl)methanol of formula 2, it dehydrates in situ under the catalysis of a chiral phosphoric acid catalyst to generate 8-methylenenaphthalen-2-imine

[0036] In some possible implementation manners, the chiral phosphoric acid catalyst is selected from The substituents at the 3-position and 3'-position of the binaphthyl skeleton of the chiral phosphoric acid catalyst are 2,4,6-tricyclopentylphenyl; this chiral phosphoric acid catalyst can act as a Bronsted acid to dehydrate the substrate compound A and in situ generate a novel naphthoquinone intermediate based on the naphthalene ring. Moreover, by using a chiral phosphoric acid catalyst with 2,4,6-tricyclopentylphenyl substituents at 3,3', the expected product can be obtained with good enantioselectivity in the subsequent asymmetric addition reaction.

[0037] In some possible implementation manners, the dosage of the chiral phosphoric acid catalyst is 5-10 mol% of the molar dosage of compound A; in this case, the dosage of the chiral phosphoric acid catalyst can efficiently catalyze the dehydration of compound A to in situ generate a novel naphthoquinone intermediate based on the naphthalene ring.

[0038] In some specific embodiments, when compound A is selected from 8-(hydroxy(aryl)methyl)naphthalen-2-ol of Formula 1, the amount of the chiral phosphoric acid catalyst used is 5-8 mol%. This amount of the chiral phosphoric acid catalyst fully ensures the catalytic dehydration effect on 8-(hydroxy(aryl)methyl)naphthalen-2-ol. Exemplarily, the amount of the chiral phosphoric acid catalyst used can be 5-6 mol%, 6-7 mol%, 7-8 mol%, etc. If the amount of the chiral phosphoric acid catalyst used is too small, the ee value (enantiomeric excess) and the yield will decrease; if the amount of the chiral phosphoric acid catalyst used is too large, it is not helpful for improving the enantioselectivity and yield of the product.

[0039] In some specific embodiments, when compound A is selected from (7-aminonaphthalen-1-yl)(aryl)methanol of Formula 2, the amount of the chiral phosphoric acid catalyst used is 8-10 mol%. Since aminonaphthalene has a certain basicity, it will reduce the activity of the chiral phosphoric acid catalyst. Therefore, increasing the amount of the chiral phosphoric acid catalyst used is beneficial to fully ensure the catalytic dehydration effect on (7-aminonaphthalen-1-yl)(aryl)methanol. If the amount of the chiral phosphoric acid catalyst used is too small, the ee value (enantiomeric excess) and the yield will decrease; if the amount of the chiral phosphoric acid catalyst used is too large, it is not helpful for improving the enantioselectivity and yield of the product.

[0040] In some possible implementation manners, the steps of the dehydration treatment include: after dissolving and dispersing compound A, the chiral phosphoric acid catalyst, and the molecular sieve in a first organic solvent, performing a mixing treatment at a temperature of 0-25 °C to dehydrate compound A by one molecule of water to obtain a novel naphthoquinone intermediate. Under this condition, it can fully ensure that the chiral phosphoric acid catalyst acts as a Bronsted acid to dehydrate the substrate compound A and in-situ generate a novel naphthoquinone intermediate based on the naphthalene ring. Among them, the purpose of adding the molecular sieve is to absorb the water molecules existing or newly generated in the reaction and improve or ensure the reaction efficiency and yield.

[0041] In some possible implementation manners, the molecular sieve is selected from molecular sieve; The pore diameter of the molecular sieve is able to adsorb any molecule smaller than this pore diameter, especially suitable for pressure swing adsorption separation and co-adsorption of water and carbon dioxide. Based on the industrial application characteristics of the molecular sieve, the molecular sieve has high selective adsorption, fast adsorption rate, and is especially suitable for pressure swing adsorption.

[0042] In some possible implementation manners, in the hybrid treatment system, the concentration of the molecular sieve is 80-120 mg / mmol. The molecular sieve at this concentration can fully ensure the absorption of the existing or newly generated water molecules in the reaction, improving the reaction efficiency and yield. By way of example, when the concentration of the molecular sieve is 100 mg / mmol, it means that 100 mg of the molecular sieve needs to be added in a reaction with a specification of 1 mmol. Specifically, the concentration of the molecular sieve can be 80-90 mg / mmol, 90-100 mg / mmol, 100-110 mg / mmol, 110-120 mg / mmol, etc.

[0043] In some possible implementation manners, the first organic solvent includes one of dichloromethane, dichloroethane, and chlorobenzene; these organic solvents are organic solvents that do not chemically react with the reactants and have high solubility in components such as the chiral phosphoric acid catalyst and compound A, providing a suitable solvent environment for the catalytic dehydration reaction.

[0044] In some possible implementation manners, in the hybrid treatment system, the concentration of compound A is 0.050-0.1 mol / L, and this concentration of compound A is beneficial to the reaction efficiency and yield. Specifically, the concentration of compound A can be 0.05-0.06 mol / L, 0.06-0.07 mol / L, 0.07-0.08 mol / L, 0.08-0.09 mol / L, 0.09-0.1 mol / L, etc.

[0045] In a second aspect, an embodiment of the present application provides a novel naphthoquinone intermediate prepared by the above method. The structural general formula of the novel naphthoquinone intermediate is wherein, R 1' , R 2' are each independently selected from one of hydrogen, alkyl, and ether, X is O or NR 3' , and R 3' is one of hydrogen and acyl.

[0046] The novel naphthoquinone intermediate of the embodiment of the present application is prepared by the above method. The prepared novel naphthoquinone intermediate has excellent electrophilic properties and can participate in asymmetric organic catalytic reactions as an electrophilic reagent. It expands the naphthoquinone intermediate and improves the application of the naphthoquinone intermediate in asymmetric addition reactions.

[0047] In a third aspect, an embodiment of the present application provides a method for preparing a chiral naphthalene compound, including the following steps:

[0048] S20. Dissolve compound A, the chiral phosphoric acid catalyst, and the nucleophile in a second organic solvent for a mixing reaction, and perform nucleophilic substitution after in-situ generation of the novel naphthoquinone intermediate to obtain the chiral naphthalene compound; the structural general formula of compound A is The structural general formula of the chiral naphthalene compound is Among them, R 1' , R 2' are each independently selected from one of hydrogen, alkyl, and ether, X is O or NR 3' , R 3' is one of hydrogen and acyl group, and R 4' is a nucleophilic group.

[0049] In the preparation method of the chiral naphthalene compound according to the embodiment of the present application, compound A, a chiral phosphoric acid catalyst, and a nucleophilic reagent are dissolved in an organic solvent and then subjected to a mixing reaction. During the mixing reaction, first, the chiral phosphoric acid catalyst acts as a Bronsted acid to dehydrate the substrate compound A in situ to generate a novel naphthoquinone intermediate based on the naphthalene ring. This intermediate has strong electrophilic properties, a large energy, and is difficult to exist stably. It is easily attacked by the nucleophilic reagent. In the reaction system, the nucleophilic reagent attacks the novel naphthoquinone intermediate. At this time, the chiral phosphoric acid catalyst acts as a Lewis base to assist in enhancing the nucleophilicity of the nucleophilic reagent. At the same time, due to the presence of large steric hindrance groups on both sides, the attack direction of the nucleophilic reagent is restricted, thereby controlling the stereoselectivity of the product. After the novel naphthoquinone intermediate is subjected to nucleophilic substitution, a chiral naphthalene compound is obtained. The present application uses the in-situ generated novel naphthoquinone intermediate electrophile based on the naphthalene ring and the nucleophilic reagent to synthesize the chiral naphthalene compound in one step, which has important application value. Moreover, this reaction undergoes the reaction mechanism of methylene quinone and has important guiding significance for subsequent reactions of the same type.

[0050] In some possible implementation manners, compound A is selected from at least one of them; among them, R 1 , R 2 , R 8 , R 9 are each independently selected from one of hydrogen, alkyl, and ether, and R 7 is selected from one of acyl groups. Specifically, in the structure of formula 1, R 1 is one of hydrogen, alkyl, and ether. More specifically, the alkyl substituent includes but is not limited to methyl, and the ether includes but is not limited to methoxy group. R 2 is one of hydrogen, alkyl, and ether. The alkyl substituent includes but is not limited to methyl, and the ether includes but is not limited to methoxy group and methylthio group. In the structure of formula 2, R 7 is one of acyl groups. More specifically, the acyl substituent is 1-adamantyl acyl group. R 8 is one of hydrogen, alkyl, and ether. More specifically, the alkyl substituent includes but is not limited to methyl, and the ether includes but is not limited to methoxy group. R 9 is one of hydrogen, alkyl, and ether. The alkyl substituent includes but is not limited to methyl, and the ether includes but is not limited to methoxy group and methylthio group.

[0051] In some possible implementation manners, the nucleophile includes at least one of indoles and carbazoles. Since the novel naphthoquinone intermediate based on naphthalene ring generated in situ in the embodiments of the present application has a relatively high energy and is difficult to exist stably, nucleophiles such as indole or carbazole are used to capture the high-energy intermediate, and a chiral naphthalene compound product with a relatively low energy and stable existence is obtained. Moreover, there are relatively few methods for the stereoselective N-alkylation of indole and carbazole, and this method expands the cases of stereoselective N-alkylation.

[0052] In some possible implementation manners, the nucleophile includes at least one of; wherein, R 3 and R 4 are each independently selected from one of alkyl and aryl, and R 5 and R 6 are each independently selected from one of alkyl, aryl, halogen, and ether. Specifically, in the formula 3 structure of indole, R 3 is one of alkyl and aryl. More specifically, the alkyl includes but is not limited to methyl and ethyl, and the aryl includes but is not limited to phenyl. R 4 is one of alkyl and aryl. More specifically, the alkyl includes but is not limited to methyl and ethyl, and the aryl includes but is not limited to phenyl. R 5 is one of halogen, alkyl, and aryl. More specifically, the halogen includes but is not limited to fluorine, chlorine, and bromine, the alkyl includes but is not limited to methyl and ethyl, and the aryl includes but is not limited to phenyl. In the formula 4 structure of carbazole, R 6 is one of halogen, alkyl, and aryl. More specifically, the halogen includes but is not limited to fluorine, chlorine, and bromine, the alkyl includes but is not limited to methyl and ethyl, and the aryl includes but is not limited to phenyl.

[0053] In some possible implementation manners, the chiral phosphoric acid catalyst is selected from The substituents at the 3-position and 3'-position of the binaphthyl skeleton of the chiral phosphoric acid catalyst are 2,4,6-tricyclopentylphenyl. In the embodiments of the present application, due to the above technical difficulties existing in the process of the enantioselective functionalization reaction of the unactivated sp 3 N-H bond of indole in the organic catalysis, it can be seen that the selection of the catalyst plays an important role in the whole reaction. By using a chiral phosphoric acid catalyst with 2,4,6-tricyclopentylphenyl substituents at 3,3', the expected product can be obtained with good enantioselectivity.

[0054] In some possible implementation manners, the dosage of the chiral phosphoric acid catalyst is 5-10 mol% of the molar dosage of compound A. In this case, the dosage of the chiral phosphoric acid catalyst can efficiently catalyze the dehydration of compound A to generate a novel naphthoquinone intermediate based on naphthalene ring in situ, and enhance the nucleophilicity of the nucleophile to attack the electrophile of the novel naphthoquinone intermediate, control the stereoselectivity of the product, and obtain a chiral naphthalene compound.

[0055] In some possible implementation manners, the temperature condition of the mixed reaction is 0 to 25 °C. Under this condition, the generation efficiency and yield of the chiral naphthalene compound can be fully ensured.

[0056] In some possible implementation manners, a molecular sieve with a concentration of 80 to 120 mg / mmol is further added to the mixed reaction system. The purpose of adding the molecular sieve is to absorb the water molecules existing or newly generated in the reaction, and improve or ensure the reaction efficiency and yield. In some specific implementation manners, the molecular sieve is selected from molecular sieves. In some specific implementation manners, in the mixed treatment system, the concentration of the molecular sieve is 80 to 120 mg / mmol.

[0057] In some possible implementation manners, the second organic solvent includes one of dichloromethane, dichloroethane, and chlorobenzene. These organic solvents are organic solvents that do not chemically react with the reactants, and have high solubility in components such as the chiral phosphoric acid catalyst, compound A, and nucleophile, providing a suitable solvent environment for the mixed reaction. In some possible implementation manners, in the mixed treatment system, the concentration of compound A is 0.050 to 0.1 mol / L, and this concentration of compound A is beneficial to the reaction efficiency and yield.

[0058] In some possible implementation manners, the chiral naphthalene compound includes

[0059] at least one of

[0060] In some specific embodiments, 8-(hydroxy(aryl)methyl)naphthalen-2-ol (Formula 1), 2,3-disubstituted indole (Formula 3), chiral phosphoric acid catalyst, and molecular sieve are dissolved in an organic solvent, and an asymmetric functionalization reaction of the unactivated sp3 nitrogen-hydrogen bond of indole is carried out under stirring at 0 °C. 8-(hydroxy(aryl)methyl)naphthalen-2-ol is in-situ generated into 8-methylene naphthalen-2-one, and reacts with indole to obtain chiral 8-((1H-indol-1-yl)(aryl)methyl)naphthalen-2-ol shown in Formula 6. The reaction formula is as follows:

[0061]

[0062] In some specific embodiments, 8-(hydroxy(aryl)methyl)naphthalen-2-ol (Formula 1), carbazole (Formula 4), chiral phosphoric acid catalyst, The molecular sieve is dissolved in an organic solvent, and the asymmetric functionalization reaction of the unactivated sp3 N-H bond of carbazole is carried out under stirring at room temperature of 25 °C. 8-(Hydroxy(aryl)methyl)naphthalen-2-ol is in-situ generated to 8-methylene naphthalen-2-one, and reacts with carbazole to obtain the chiral 8-((9H-carbazol-1-yl)(aryl)methyl)naphthalen-2-ol shown in Formula 7. The reaction formula is as follows:

[0063]

[0064] In some specific embodiments, when compound A is 8-(hydroxy(aryl)methyl)naphthalen-2-ol of Formula 1, the dosage of the chiral phosphoric acid catalyst is 5-8 mol%. If the dosage of the chiral phosphoric acid catalyst is too small, the ee value (enantiomeric excess) and the yield will decrease; if the dosage of the chiral phosphoric acid catalyst is too large, it is not helpful for improving the enantioselectivity and yield of the product.

[0065] In some specific embodiments, (7-aminonaphthalen-1-yl)(aryl)methanol (Formula 2), 2,3-disubstituted indole (Formula 3), chiral phosphoric acid catalyst, The molecular sieve is dissolved in an organic solvent, and the asymmetric functionalization reaction of the unactivated sp 3 N-H bond of indole is carried out under stirring at room temperature of 25 °C. (7-aminonaphthalen-1-yl)(aryl)methanol is in-situ generated to 8-methylene naphthalen-2-imine, and reacts with indole to obtain the chiral 8-((1H-indol-1-yl)(aryl)methyl)naphthalen-2-amine shown in Formula 8. The reaction formula is as follows:

[0066]

[0067] In some specific embodiments, (7-aminonaphthalen-1-yl)(aryl)methanol (Formula 2), carbazole (Formula 4), chiral phosphoric acid catalyst, The molecular sieve is dissolved in an organic solvent, and the asymmetric functionalization reaction of the unactivated sp3 N-H bond of carbazole is carried out under stirring at room temperature of 25 °C. (7-aminonaphthalen-1-yl)(aryl)methanol is in-situ generated to 8-methylene naphthalen-2-imine, and reacts with carbazole to obtain the chiral 8-((9H-carbazol-1-yl)(aryl)methyl)naphthalen-2-amine shown in Formula 9. The reaction formula is as follows:

[0068]

[0069] In some specific embodiments, when compound A is (7-aminonaphthalen-1-yl)(aryl)methanol of formula 2, the amount of the chiral phosphoric acid catalyst used is 8-10 mol%. Since aminonaphthalene has certain basicity, which will reduce the activity of the chiral phosphoric acid catalyst, increasing the amount of the chiral phosphoric acid catalyst is beneficial to fully ensure the catalytic dehydration effect on (7-aminonaphthalen-1-yl)(aryl)methanol. If the amount of the chiral phosphoric acid catalyst used is too small, the ee value (enantiomeric excess) and the yield will decrease; if the amount of the chiral phosphoric acid catalyst used is too large, it will not help to improve the enantioselectivity and yield of the product.

[0070] In some specific embodiments, the chiral naphthalene compounds include at least one of

[0071] Fourthly, an embodiment of the present application provides a chiral naphthalene compound prepared by the above method, and the general structural formula of the chiral naphthalene compound is wherein, R 1' , R 2' are each independently selected from one of hydrogen, alkyl, and ether, X is O or NR 3' , R 3' is one of hydrogen and acyl, and R 4' is a nucleophilic group.

[0072] The chiral naphthalene compound of the embodiment of the present application is prepared by the method of the above embodiment. A novel naphthoquinone intermediate electrophile based on the naphthalene ring is generated in situ and reacts with a nucleophilic reagent to synthesize the chiral naphthalene compound in one step, which has important application value. Moreover, the reaction mechanism of methylenequinone has important guiding significance for subsequent reactions of the same type.

[0073] To enable those skilled in the art to clearly understand the above implementation details and operations of the present application, and to significantly reflect the advanced performance of the chiral naphthalene compound and its preparation method of the embodiment of the present application, the following technical solutions will be illustrated by multiple examples.

[0074] Example 1

[0075] A chiral naphthalene compound Using 8-(hydroxy(aryl)methyl)naphthalen-2-ol with R 1 being hydrogen and R 2 being methoxy and 2,3-disubstituted indole with R 3 being methyl, R 4 being methyl, and R 5 being hydrogen as reaction raw materials, and reacting with a chiral phosphoric acid catalyst. Its preparation steps include:

[0076] 8-(Hydroxy(p-methoxyphenyl)methyl)naphthalen-2-ol (84.0 mg, 0.30 mmol), 2,3-dimethylindole (65.3 mg, 0.45 mmol), chiral phosphoric acid (13.5 mg, 0.015 mmol) and molecular sieve (30 mg) were dissolved in dichloromethane (3 mL), and the reaction was carried out at 0 °C for 72 hours. The reaction solution was filtered through silica gel, rinsed with diethyl ether, concentrated and then subjected to silica gel column chromatography to obtain 106.1 mg of solid product. The calculated yield was 87%, and the measured ee value was 98%. The reaction equation is as follows:

[0077]

[0078] The obtained solid product was analyzed by measuring the specific rotation, determining the ee value by high performance liquid chromatography analysis, nuclear magnetic resonance and high resolution mass spectrometry. Among them, the test analysis is as follows:

[0079] 1. Specific rotation [α] measured at the D line at 25 °C D 25 : -23.0 (c = 1.0, CH2Cl2).

[0080] 2. Determination of the ee value by high performance liquid chromatography analysis: Chiral column Daicel AD column; 10% i-PrOH in hexanes; 1.0 mL / min; retention time: 11.7 min (major), 15.8 min (minor). The calculated result was 98% ee.

[0081] 3. 1H NMR and 13C NMR spectra for nuclear magnetic resonance analysis:

[0082] 1 H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 9.2 Hz, 2H), 7.46 (d, J = 7.6 Hz, 1H), 7.25 (s, 1H), 7.14 (d, J = 7.6 Hz, 1H), 7.00 - 6.93 (m, 5H), 6.88 - 6.82 (m, 2H), 6.76 - 6.71 (m, 3H), 5.47 (s, 1H), 3.68 (s, 3H), 2.22 (s, 3H), 2.03 (s, 3H) ppm.

[0083] 1313C NMR (100 MHz, CDCl3) δ 159.0, 154.1, 136.8, 134.2, 133.6, 132.8, 131.8, 130.9, 130.0, 129.2, 129.1, 128.5, 127.2, 123.2, 120.8, 118.8, 118.0, 117.7, 114.1, 110.8, 108.0, 106.1, 60.1, 55.3, 11.7, 9.1 ppm.

[0084] 4. High-resolution mass spectrometry: HRMS (CI+) Calcd for C 28 H 25 NNaO2 + [M+Na] + : 430.1778, Found: 430.1783.

[0085] It can be seen from the results that its theoretical mass is 430.1778, while the observed value of the peak found in the actual mass spectrometry is 430.1783; combined with nuclear magnetic resonance analysis, the structure of the product can be determined to be the product of this example.

[0086] Example 2

[0087] A chiral naphthalene compound R 2 is 8-(hydroxy(aryl)methyl)naphthalen-2-ol with a methoxy group and R 3 is methyl, R 4 is methyl, R 5 is 2,3-disubstituted indole with a 5-methyl group as the reaction raw material, and the reaction is carried out with a chiral phosphoric acid catalyst. Its preparation steps include:

[0088] Dissolve 8-(hydroxy(p-methoxyphenyl)methyl)naphthalen-2-ol (84.0 mg, 0.30 mmol), 2,3,5-trimethylindole (71.6 mg, 0.45 mmol), chiral phosphoric acid (13.5 mg, 0.015 mmol) and molecular sieve (30 mg) in dichloromethane (3 mL). React at 0 °C for 72 hours, filter the reaction solution through silica gel, wash with diethyl ether, concentrate, and obtain 119.5 mg of solid product by silica gel column chromatography. The calculated yield is 95%, and the measured ee value is 95%. The reaction equation is as follows:

[0089]

[0090] The obtained solid product was analyzed by measuring the specific rotation, analyzing the ee value by high-performance liquid chromatography, nuclear magnetic resonance, and high-resolution mass spectrometry. Among them, the test analysis is as follows:

[0091] 1. Specific rotation [α] measured for the D line at 25 °C D 25 : -27.0 (c = 1.0, CH2Cl2).

[0092] 2. Determination of the ee value by high performance liquid chromatography analysis: Chiral column Daicel IC column; 5% i-PrOH in hexanes; 1.0 mL / min; retention times: 4.9 min (major), 7.1 min (minor). The calculated result is 95% ee.

[0093] 3. 1H NMR and 13C NMR spectra for nuclear magnetic resonance analysis:

[0094] 1 H NMR (400 MHz, CDCl3) δ 7.70 (t, J = 9.6 Hz, 2H), 7.23 (d, J = 21.2 Hz, 2H), 7.13 (t, J = 7.6 Hz, 1H), 6.94 (t, J = 8.0 Hz, 4H), 6.86 (d, J = 7.2 Hz, 1H), 6.74 (d, J = 8.0 Hz, 2H), 6.65 (d, J = 8.0 Hz, 1H), 6.55 (d, J = 8.0 Hz, 1H), 5.44 (s, 1H), 3.68 (s, 3H), 2.36 (s, 3H), 2.20 (s, 3H), 2.03 (s, 3H) ppm.

[0095] 13 C NMR (100 MHz, CDCl3) δ 158.9, 154.0, 135.2, 134.3, 133.6, 132.8, 131.9, 130.9, 130.0, 129.4, 129.1, 128.4, 127.9, 127.2, 123.2, 122.2, 117.8, 117.7, 114.0, 110.6, 107.4, 106.1, 60.0, 55.3, 21.5, 11.6, 9.1 ppm.

[0096] 4. High resolution mass spectrometry: HRMS (CI+) Calcd for C 29 H 26 NO2 - [M - H] - : 420.1969, Found: 420.1966.

[0097] It can be seen from this result that the theoretical mass is 420.1969, while the observed value of the peak found in the actual mass spectrum is 420.1966; combined with nuclear magnetic resonance analysis, the structure of the product can be determined to be the product of this example.

[0098] Example 3

[0099] A chiral naphthalene compound Using R 1 is hydrogen, R 2 is methoxy 8-(hydroxy(aryl)methyl)naphthalen-2-ol and R 3 is methyl, R 4 is methyl, R 5 is 5-bromo 2,3-disubstituted indole as the reaction raw material, and the reaction is carried out with a chiral phosphoric acid catalyst. The preparation steps include:

[0100] Dissolve 8-(hydroxy(p-methoxyphenyl)methyl)naphthalen-2-ol (84.0 mg, 0.30 mmol), 2,3-dimethyl-5-bromoindole (100.8 mg, 0.45 mmol), chiral phosphoric acid (13.5 mg, 0.015 mmol) and molecular sieve (30 mg) in dichloromethane (3 mL). React at 0 °C for 72 hours. Filter the reaction solution through silica gel, wash with diethyl ether, concentrate, and obtain 137.2 mg of solid product by silica gel column chromatography. The calculated yield is 94%, and the measured ee value is 96%. The reaction equation is as follows:

[0101]

[0102] Analyze the obtained solid product, and the analysis methods include measuring the specific rotation, determining the ee value by high-performance liquid chromatography analysis, nuclear magnetic resonance, and high-resolution mass spectrometry. Among them, the test analysis is as follows:

[0103] 1. Specific rotation [α] measured at 25 °C on the D line D 25 :+10.2 (c = 1.0, CH2Cl2).

[0104] 2. Determining the ee value by high-performance liquid chromatography analysis: Chiral column Daicel IC column; 5% i-PrOH in hexanes; 1.0 mL / min; retention time: 5.4 min (major), 8.4 min (minor). The calculated result is 96% ee.

[0105] 3. 1H NMR and 13C NMR analysis of nuclear magnetic resonance:

[0106] 11H NMR (400 MHz, CDCl3) δ 7.77 - 7.72 (m, 2H), 7.58 (d, J = 1.6 Hz, 1H), 7.22 - 7.14 (m, 2H), 7.03 (dd, J1 = 9.2 Hz, J2 = 2.4 Hz, 1H), 6.93 - 6.86 (m, 4H), 6.82 - 6.76 (m, 3H), 6.46 (d, J = 8.8 Hz, 1H), 5.39 (s, 1H), 3.72 (s, 3H), 2.18 (s, 3H), 2.08 (s, 3H) ppm.

[0107] 13 13C NMR (100 MHz, CDCl3) δ 159.1, 154.1, 135.5, 134.9, 133.8, 132.7, 131.3, 131.0 (2C), 130.0, 129.1, 128.7, 127.1, 123.4, 123.2, 120.6, 117.8, 114.2, 112.4, 112.2, 107.7, 105.9, 60.2, 55.3, 11.6, 9.0 ppm.

[0108] 4. High - resolution mass spectrometry: HRMS (CI+) Calcd for C 28 H 23 BrNO2 - [M - H] - : 484.0918, Found: 484.0917.

[0109] It can be seen from this result that its theoretical mass is 484.0918, while the observed value of the peak found in the actual mass spectrum is 484.0917; combined with nuclear magnetic resonance analysis, the product structure can be determined to be the product of this example.

[0110] Example 4

[0111] A chiral naphthalene compound Using 8 - (hydroxy(aryl)methyl)naphthalen - 2 - ol with R 1 being hydrogen, R 2 being methoxy, and 2,3 - disubstituted indole with R 3 being methyl, R 4 being methyl, R 5 being 5 - chloro as reaction raw materials, reacting with a chiral phosphoric acid catalyst, and its preparation steps include:

[0112] 8 - (Hydroxy(p - methoxyphenyl)methyl)naphthalen - 2 - ol (84.0 mg, 0.30 mmol), 2,3 - dimethyl - 5 - chloroindole (80.8 mg, 0.45 mmol), chiral phosphoric acid (13.5 mg, 0.015 mmol) and The molecular sieve (30 mg) was dissolved in dichloromethane (3 mL). The reaction was carried out at 0 °C for 72 hours. The reaction solution was filtered through silica gel, rinsed with ether, concentrated, and then purified by silica gel column chromatography to obtain 130.7 mg of the solid product. The calculated yield was 99%, and the measured ee value was 98%. The reaction equation is as follows:

[0113]

[0114] The obtained solid product was analyzed by measuring the specific rotation, determining the ee value by high performance liquid chromatography analysis, nuclear magnetic resonance, and high resolution mass spectrometry. Among them, the test analysis is as follows:

[0115] 1. Specific rotation [α] measured at the D line at 25 °C D 25 :+10.0 (c = 1.0, CH2Cl2).

[0116] 2. Determination of the ee value by high performance liquid chromatography analysis: Chiral column Daicel IC column; 5% i-PrOH in hexanes; 1.0 mL / min; retention time: 5.4 min (major), 8.1 min (minor). The calculated result was 98% ee.

[0117] 3. 1H NMR and 13C NMR spectra for nuclear magnetic resonance analysis:

[0118] 1 H NMR (400 MHz, CDCl3) δ 7.73 (t, J = 9.2 Hz, 2H), 7.41 (d, J = 1.6 Hz, 1H), 7.20 (s, 1H), 7.15 (t, J = 7.6 Hz, 1H), 7.01 (dd, J1 = 8.8 Hz, J2 = 2.0 Hz, 1H), 6.95 - 6.90 (m, 3H), 6.82 (d, J = 7.2 Hz, 1H), 6.76 - 6.73 (m, 3H), 6.50 (d, J = 8.8 Hz, 1H), 5.63 (s, 1H), 3.70 (s, 3H), 2.17 (s, 3H), 2.07 (s, 3H) ppm.

[0119] 13 C NMR (100 MHz, CDCl3) δ 159.1, 154.1, 135.2, 135.1, 133.8, 132.7, 131.4, 131.0, 130.4, 130.0, 129.1, 128.7, 127.1, 124.5, 123.2, 120.8, 117.8, 117.5, 114.1, 111.9, 107.7, 106.0, 60.2, 55.3, 11.6, 9.0 ppm.

[0120] 4. High-resolution mass spectrometry: HRMS(CI+) Calcd for C 28 H 23 ClNO2 - [M-H] - : 440.1423, Found: 440.1414.

[0121] It can be seen from this result that its theoretical mass is 440.1423, while the observed value of the peak found in the actual mass spectrometry is 440.1414; combined with nuclear magnetic resonance analysis, the product structure can be determined to be the product of this example.

[0122] Example 5

[0123] A chiral naphthalene compound Using R 1 being hydrogen, R 2 being methoxy, 8-(hydroxy(aryl)methyl)naphthalen-2-ol and R 3 being phenyl, R 4 being methyl, R 5 being hydrogen, 2,3-disubstituted indole as reaction raw materials, reacting with a chiral phosphoric acid catalyst, and its preparation steps include:

[0124] Dissolve 8-(hydroxy(p-methoxyphenyl)methyl)naphthalen-2-ol (84.0 mg, 0.30 mmol), 2-phenyl-3-methylindole (93.3 mg, 0.45 mmol), chiral phosphoric acid (13.5 mg, 0.015 mmol) and molecular sieve (30 mg) in dichloromethane (3 mL). React at 0 °C for 72 hours, filter the reaction solution through silica gel, wash with ether, concentrate, and obtain 130.7 mg of solid product by silica gel column chromatography. The calculated yield is 75%, and the measured ee value is 99%. The reaction equation is as follows:

[0125]

[0126] Analyze the obtained solid product, and the analysis methods include measuring the specific rotation, determining the ee value by high-performance liquid chromatography analysis, nuclear magnetic resonance, and high-resolution mass spectrometry. Among them, the test analysis is as follows:

[0127] 1. Specific rotation [α] measured at the D line at 25 °C D 25 : +195.4 (c = 1.0, CH2Cl2).

[0128] 2. Determining the ee value by high-performance liquid chromatography analysis: Chiral column Daicel IC column; 5% i-PrOH in hexanes; 1.0 mL / min; retention time: 4.8 min (major), 5.9 min (minor). The calculated result is 99% ee.

[0129] 3. 1H-NMR and 13C-NMR spectra for nuclear magnetic resonance analysis:

[0130] 1 H NMR (400 MHz, CDCl3) δ 7.71 - 7.69 (m, 2H), 7.58 (d, J = 7.6 Hz, 1H), 7.29 (d, J = 7.2 Hz, 1H), 7.24 - 7.14 (m, 6H), 7.06 - 7.02 (m, 2H), 6.95 - 6.87 (m, 2H), 6.82 (t, J = 9.2 Hz, 3H), 6.63 (d, J = 8.8 Hz, 3H), 5.07 (s, 1H), 3.65 (s, 3H), 2.28 (s, 3H) ppm.

[0131] 13 C NMR (100 MHz, CDCl3) δ 158.6, 153.8, 138.7, 136.7, 134.4, 132.5, 132.4, 132.1, 130.7 (2C), 129.9, 129.5, 129.1, 128.4, 128.3, 128.1, 127.3, 123.2, 121.7, 119.2, 118.8, 117.5, 113.8, 113.0, 109.6, 106.3, 60.6, 55.3, 9.7 ppm.

[0132] 4. High-resolution mass spectrometry: HRMS (CI+) Calcd for C 33 H 26 NO2 - [M - H] - : 468.1969, Found: 468.1961.

[0133] It can be seen from this result that the theoretical mass is 468.1969, while the observed value of the peak found in the actual mass spectrum is 468.1961; combined with nuclear magnetic resonance analysis, the product structure can be determined to be the product of this example.

[0134] Example 6

[0135] A chiral naphthalene compound Using 8-(hydroxy(aryl)methyl)naphthalen-2-ol with R 1 being hydrogen, R 2 being methoxy and R 3 being phenyl, R 4 being methyl, R5 Using 2,3-disubstituted indole of chlorine as a reaction raw material and carrying out the reaction with a chiral phosphoric acid catalyst, the preparation steps include:

[0136] Dissolve 8-(hydroxy(p-methoxyphenyl)methyl)naphthalen-2-ol (84.0 mg, 0.30 mmol), 2-phenyl-3-methyl-5-chloroindole (108.8 mg, 0.45 mmol), chiral phosphoric acid (13.5 mg, 0.015 mmol) and molecular sieve (30 mg) in dichloromethane (3 mL). React at 0 °C for 72 hours, filter the reaction solution through silica gel, wash with diethyl ether, concentrate and then carry out silica gel column chromatography to obtain 119.2 mg of solid product. The calculated yield is 79%, and the measured ee value is 99%. The reaction equation is as follows:

[0137]

[0138] Analyze the obtained solid product, and the analysis methods include measuring the specific rotation, analyzing the ee value by high performance liquid chromatography, nuclear magnetic resonance and high resolution mass spectrometry. Among them, the test analysis is as follows:

[0139] 1. Specific rotation [α] measured at the D line at 25 °C D 25 : +139.4 (c = 1.0, CH2Cl2).

[0140] 2. Analyzing the ee value by high performance liquid chromatography: Chiral column Daicel IC column; 5% i-PrOH in hexanes; 1.0 mL / min; retention time: 4.8 min (major), 5.9 min (minor). The calculated result is 99% ee.

[0141] 3. 1H NMR and 13C NMR analysis:

[0142] 1 H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 2.0 Hz, 1H), 7.26 - 7.14 (m, 7H), 7.00 (s, 1H), 6.96 (dd, J1 = 8.8 Hz, J2 = 2.0 Hz, 1H), 6.82 (dd, J1 = 8.8 Hz, J2 = 2.0 Hz, 3H), 6.69 - 6.63 (m, 4H), 5.21 (s, 1H), 3.66 (s, 3H), 2.22 (s, 3H) ppm.

[0143] 1313C NMR (100 MHz, CDCl3) δ 158.7, 153.9, 140.1, 135.1, 134.1, 132.4, 131.9, 131.8, 130.8, 130.7, 130.6, 129.8, 129.1, 128.54, 128.50, 128.4, 127.1, 124.9, 123.1, 121.9, 118.3, 117.6, 113.93, 113.88, 109.3, 106.2, 60.8, 55.3, 9.6 ppm.

[0144] 4. High-resolution mass spectrometry: HRMS (CI+) Calcd for C 33 H 25 ClNO2 - [M - H] - : 502.1579, Found: 502.1570.

[0145] It can be seen from this result that its theoretical mass is 502.1579, while the observed value of the peak found in the actual mass spectrum is 502.1570; combined with nuclear magnetic resonance analysis, the product structure can be determined to be the product of this example.

[0146] Example 7

[0147] A chiral naphthalene compound Using R 1 being hydrogen, R 2 being methoxy, 8-(hydroxy(aryl)methyl)naphthalen-2-ol and R 3 being phenyl, R 4 being phenyl, R 5 being hydrogen, 2,3-disubstituted indole as reaction raw materials, reacting with a chiral phosphoric acid catalyst, and its preparation steps include:

[0148] Dissolve 8-(hydroxy(p-methoxyphenyl)methyl)naphthalen-2-ol (84.0 mg, 0.30 mmol), 2,3-diphenylindole (121.2 mg, 0.45 mmol), chiral phosphoric acid (13.5 mg, 0.015 mmol) and molecular sieve (30 mg) in dichloromethane (3 mL). React at 0 °C for 72 hours, filter the reaction solution through silica gel, wash with diethyl ether, concentrate, and obtain 118.8 mg of solid product by silica gel column chromatography. The calculated yield is 74%, and the measured ee value is 99%. The reaction equation is as follows:

[0149]

[0150] The obtained solid product was analyzed by measuring the specific rotation, determining the ee value by high performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR), and high resolution mass spectrometry (HRMS). The specific analysis methods are as follows:

[0151] 1. Specific rotation [α] measured at 25 °C using the D line D 25 : +191.8 (c = 1.0, CH2Cl2).

[0152] 2. Determination of the ee value by HPLC: Chiral column Daicel IC column; 5% i-PrOH in hexanes; 1.0 mL / min; retention times: 4.8 min (major), 5.9 min (minor). The calculated result was 99% ee.

[0153] 3. 1H NMR and 13C NMR spectra for NMR analysis:

[0154] 1 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 7.2 Hz, 1H), 7.30 (d, J = 7.6 Hz, 2H), 7.25 - 7.03 (m, 11H), 6.95 - 6.91 (m, 5H), 6.69 (d, J = 8.8 Hz, 2H), 6.63 (d, J = 2.0 Hz, 1H), 5.01 (s, 1H), 3.66 (s, 3H) ppm.

[0155] 13 13C NMR (101 MHz, CDCl3) δ 158.8, 153.8, 138.7, 136.9, 135.2, 134.1, 132.4, 132.3, 131.8, 131.3, 130.8, 130.1, 130.0, 129.1, 128.5, 128.4, 128.3, 128.2, 128.1, 127.4, 125.7, 123.2, 122.1, 120.1, 119.7, 117.6, 116.2, 113.9, 113.4, 106.2, 60.7, 55.3 ppm.

[0156] 4. High resolution mass spectrometry: HRMS (CI+) Calcd for C 38 H 28 NO2 - [M - H] - : 530.2126, Found: �30.2131.

[0157] It can be seen from the results that the theoretical mass is 530.2126, while the observed value of the peak found in the actual mass spectrometry is 530.2131; combined with nuclear magnetic resonance analysis, the product structure can be determined to be the product of this example.

[0158] Example 8

[0159] A chiral naphthalene compound Using R 1 is hydrogen, R 2 is methoxy 8-(hydroxy(aryl)methyl)naphthalen-2-ol and R 3 is phenyl, R 4 is phenyl, R 5 is 5-methoxy 2,3-disubstituted indole as the reaction raw material, and the reaction is carried out with a chiral phosphoric acid catalyst. The preparation steps include:

[0160] Dissolve 8-(hydroxy(p-methoxyphenyl)methyl)naphthalen-2-ol (84.0 mg, 0.30 mmol), 2,3-diphenylindole (134.7 mg, 0.45 mmol), chiral phosphoric acid (13.5 mg, 0.015 mmol) and molecular sieve (30 mg) in dichloromethane (3 mL). React at 0 °C for 72 hours. Filter the reaction solution through silica gel, wash with diethyl ether, concentrate, and obtain 126.5 mg of solid product by silica gel column chromatography. The calculated yield is 75%, and the measured ee value is 99%. The reaction equation is as follows:

[0161]

[0162] Analyze the obtained solid product. The analysis methods include measuring the specific rotation, determining the ee value by high-performance liquid chromatography analysis, nuclear magnetic resonance, and high-resolution mass spectrometry. Among them, the test analysis is as follows:

[0163] 1. Specific rotation [α] measured at the D line at 25 °C D 25 :+328.8 (c = 1.0, CH2Cl2).

[0164] 2. Determining the ee value by high-performance liquid chromatography analysis: Chiral column Daicel IC column; 5% i-PrOH in hexanes; 1.0 mL / min; retention time: 6.4 min (major), 14.9 min (minor). The calculated result is 99% ee.

[0165] 3. 1H NMR and 13C NMR analysis of nuclear magnetic resonance:

[0166] 11H NMR (400 MHz, CDCl3) δ 7.73 - 7.71 (m, 2H), 7.35 (d, J = 7.2 Hz, 1H), 7.31 - 7.13 (m, 9H), 7.09 - 7.07 (m, 4H), 6.97 (dd, J1 = 9.2 Hz, J2 = 2.4 Hz, 1H), 6.89 (d, J = 8.0 Hz, 2H), 6.78 (d, J = 8.8 Hz, 1H), 6.70 (d, J = 8.8 Hz, 2H), 6.64 (d, J = 2.0 Hz, 1H), 6.58 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 5.19 (s, 1H), 3.74 (s, 3H), 3.69 (s, 3H) ppm.

[0167] 13 13C NMR (101 MHz, CDCl3) δ 158.8, 154.3, 153.9, 139.4, 135.4, 134.2, 132.4, 132.3, 132.2, 131.8, 131.2, 130.8, 130.0, 129.9, 129.1, 128.50, 128.48, 128.4, 128.33, 128.26, 127.3, 125.6, 123.2, 117.6, 115.9, 114.2, 113.9, 112.1, 106.2, 101.3, 60.7, 55.8, 55.3 ppm.

[0168] 4. High - resolution mass spectrometry: HRMS (CI+) Calcd for C 39 H 30 NO3 - [M - H] - : 560.2231, Found: 560.2230.

[0169] It can be seen from this result that its theoretical mass is 560.2231, while the observed value of the peak found in the actual mass spectrum is 560.2230; combined with nuclear magnetic resonance analysis, the structure of the product can be determined to be the product of this example.

[0170] Example 9

[0171] A chiral naphthalene compound Using 8 - (hydroxy(aryl)methyl)naphthalene - 2 - ol with R 1 being hydrogen, R 2 being methoxy and 2,3 - disubstituted indole with R 3 being methyl, R 4 being ethyl, R 5 being 5 - bromo as reaction raw materials, reacting with a chiral phosphoric acid catalyst, and its preparation steps include:

[0172] 8-(Hydroxy(p-methoxyphenyl)methyl)naphthalen-2-ol (84.0 mg, 0.30 mmol), 2-ethyl-3-methyl-5-bromoindole (107.1 mg, 0.45 mmol), chiral phosphoric acid (13.5 mg, 0.015 mmol) and molecular sieve (30 mg) were dissolved in dichloromethane (3 mL). The reaction was carried out at 0 °C for 72 hours. The reaction solution was filtered through silica gel, rinsed with diethyl ether, concentrated and purified by silica gel column chromatography to obtain 102.0 mg of solid product. The calculated yield was 68%, and the measured ee value was 99%. The reaction equation is as follows:

[0173]

[0174] The obtained solid product was analyzed by measuring the specific rotation, determining the ee value by high performance liquid chromatography analysis, nuclear magnetic resonance and high resolution mass spectrometry. Among them, the test analysis is as follows:

[0175] 1. Specific rotation [α]D measured at 25 °C D 25 : +76.6 (c = 1.0, CH2Cl2).

[0176] 2. Determination of ee value by high performance liquid chromatography analysis: Chiral column Daicel IC column; 5% i-PrOH in hexanes; 1.0 mL / min; retention time: 4.9 min (major), 6.3 min (minor). The calculated result was 99% ee.

[0177] 3. 1H NMR and 13C NMR analysis of nuclear magnetic resonance:

[0178] 1 H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.8 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.22 (s, 1H), 7.13 (t, J = 7.6 Hz, 1H), 7.03 (dd, J1 = 8.8 Hz, J2 = 2.0 Hz, 1H), 6.98 - 6.83 (m, 5H), 6.73 (d, J = 8.4 Hz, 2H), 6.42 (d, J = 8.8 Hz, 1H), 5.43 (s, 1H), 3.70 (s, 3H), 2.73 - 2.56 (s, 2H), 2.21 (s, 3H), 0.92 (t, J = 7.2 Hz, 3H) ppm.

[0179] 1313C NMR (101 MHz, CDCl3) δ 159.1, 154.0, 140.7, 135.4, 133.8, 132.5, 131.4, 131.2, 131.0, 130.1, 129.1, 128.5, 126.6, 123.4, 123.3, 120.6, 117.7, 113.2, 112.2, 107.1, 106.1, 59.8, 55.3, 18.6, 14.3, 14.2, 8.8 ppm.

[0180] 4. High-resolution mass spectrometry: HRMS (CI+) Calcd for C 29 H 25 BrNO2 - [M-H] - : 498.1074, Found: 498.1066.

[0181] It can be seen from this result that its theoretical mass is 498.1074, while the observed value of the peak found in the actual mass spectrometry is 498.1066; combined with nuclear magnetic resonance analysis, the product structure can be determined to be the product of this example.

[0182] Example 10

[0183] A chiral naphthalene compound Using R 1 being hydrogen, R 2 being hydrogen, 8-(hydroxy(aryl)methyl)naphthalen-2-ol and R 6 being hydrogen, carbazole as reaction raw materials, reacting with a chiral phosphoric acid catalyst, and its preparation steps include:

[0184] Dissolve 8-(hydroxy(phenyl)methyl)naphthalen-2-ol (75.0 mg, 0.30 mmol), carbazole (75.2 mg, 0.45 mmol), chiral phosphoric acid (13.5 mg, 0.015 mmol) and molecular sieve (30 mg) in dichloromethane (3 mL). React at room temperature for 24 hours. Filter the reaction solution through silica gel, wash with diethyl ether, concentrate, and obtain 108.4 mg of solid product by silica gel column chromatography. The calculated yield is 90%, and the measured ee value is 93%. The reaction equation is as follows:

[0185]

[0186] Analyze the obtained solid product, and the analysis methods include measuring the specific rotation, determining the ee value by high-performance liquid chromatography analysis, nuclear magnetic resonance, and high-resolution mass spectrometry. Among them, the test analysis is as follows:

[0187] 1. Specific rotation [α] measured at the D line at 25 °C D25 : -134.0 (c = 1.0, CH2Cl2).

[0188] 2. Determination of ee value by high performance liquid chromatography: Chiral column Daicel AD column; 10% i-PrOH in hexanes; 1.0 mL / min; retention time: 13.1 min (major), 14.4 min (minor). The calculated result is 93% ee.

[0189] 3. 1H NMR and 13C NMR spectra for nuclear magnetic resonance analysis:

[0190] 1 H NMR (400 MHz, CDCl3) δ 8.05 - 8.03 (m, 2H), 7.72 (t, J = 7.6 Hz, 2H), 7.54 (s, 1H), 7.25 - 7.21 (m, 3H), 7.19 - 7.09 (m, 8H), 6.99 - 6.93 (m, 3H), 6.89 (d, J = 2.0 Hz, 1H), 5.14 (s, 1H) ppm.

[0191] 13 C NMR (101 MHz, CDCl3) δ 154.1, 141.0, 139.1, 133.3, 133.2, 131.1, 129.1, 129.0, 128.9, 128.6, 128.1, 127.7, 125.9, 123.5, 123.1, 120.3, 119.4, 117.9, 110.5, 105.6, 60.5 ppm.

[0192] 4. High resolution mass spectrometry: HRMS (CI+) Calcd for C 29 H 20 NO - [M - H] - : 398.1550, Found: 398.1544.

[0193] It can be seen from this result that the theoretical mass is 398.1550, while the observed value of the peak found in the actual mass spectrum is 398.1544; combined with nuclear magnetic resonance analysis, the product structure can be determined to be the product of this example.

[0194] Example 11

[0195] A chiral naphthalene compound Using R 1 is hydrogen, R 2 is 3-methyl 8-(hydroxy(aryl)methyl)naphthalen-2-ol and R 6Using carbazole with hydrogen as the reaction raw material and carrying out the reaction with a chiral phosphoric acid catalyst, the preparation steps include:

[0196] Dissolve 8-(hydroxy(3-methylphenyl)methyl)naphthalen-2-ol (79.2 mg, 0.30 mmol), carbazole (75.2 mg, 0.45 mmol), chiral phosphoric acid (13.5 mg, 0.015 mmol) and molecular sieve (30 mg) in dichloromethane (3 mL). React at room temperature for 3 hours. Filter the reaction solution through silica gel, wash with diethyl ether, concentrate, and obtain 103.0 mg of solid product by silica gel column chromatography. The calculated yield is 83%, and the measured ee value is 93%. The reaction equation is as follows:

[0197]

[0198] Analyze the obtained solid product. The analysis methods include measuring the specific rotation, determining the ee value by high-performance liquid chromatography analysis, nuclear magnetic resonance, and high-resolution mass spectrometry. Among them, the test analysis is as follows:

[0199] 1. Specific rotation [α] measured at the D line at 25 °C D 25 : -137.8 (c = 1.0, CH2Cl2).

[0200] 2. Determining the ee value by high-performance liquid chromatography analysis: Chiral column Daicel AD column; 20% i-PrOH in hexanes; 1.0 mL / min; retention time: 5.8 min (major), 6.5 min (minor). The calculated result is 93% ee.

[0201] 3. 1H NMR and 13C NMR analysis of nuclear magnetic resonance:

[0202] 1 H NMR (400 MHz, CDCl3) δ 8.05 - 8.03 (m, 2H), 7.72 (t, J = 7.6 Hz, 2H), 7.50 (s, 1H), 7.19 - 7.07 (m, 8H), 7.03 - 6.92 (m, 5H), 6.86 (d, J = 2.4 Hz, 1H), 5.05 (s, 1H), 2.20 (s, 3H) ppm.

[0203] 1313C NMR (100 MHz, CDCl3) δ 154.2, 141.0, 139.1, 138.6, 133.4, 133.2, 131.0, 129.3, 129.1, 128.94, 128.90, 128.8, 127.7, 125.9, 125.7, 123.5, 123.0, 120.2, 119.3, 117.9, 110.6, 105.5, 60.6, 21.6 ppm.

[0204] 4. High-resolution mass spectrometry: HRMS (CI+) Calcd for C 30 H 22 NO - [M-H] - : 412.1707, Found: 412.1696.

[0205] It can be seen from the results that the theoretical mass is 412.1707, while the observed value of the peak found in the actual mass spectrometry is 412.1696. Combining with the nuclear magnetic resonance analysis, the product structure can be determined to be the product of this example.

[0206] Example 12

[0207] A chiral naphthalene compound Using R 1 being hydrogen, R 2 being 3-methoxy, 8-(hydroxy(aryl)methyl)naphthalen-2-ol and R 6 being hydrogen, carbazole as reaction raw materials, reacting with a chiral phosphoric acid catalyst, and its preparation steps include:

[0208] Dissolve 8-(hydroxy(3-methoxyphenyl)methyl)naphthalen-2-ol (84.0 mg, 0.30 mmol), carbazole (75.2 mg, 0.45 mmol), chiral phosphoric acid (13.5 mg, 0.015 mmol) and molecular sieve (30 mg) in dichloromethane (3 mL). React at room temperature for 3 hours. Filter the reaction solution through silica gel, wash with diethyl ether, concentrate, and obtain 84.8 mg of solid product by silica gel column chromatography. The calculated yield is 66%, and the measured ee value is 94%. The reaction equation is as follows:

[0209]

[0210] Analyze the obtained solid product, and the analysis methods include measuring the specific rotation, determining the ee value by high-performance liquid chromatography analysis, nuclear magnetic resonance, and high-resolution mass spectrometry. Among them, the test analysis is as follows:

[0211] 1. Specific rotation [α] measured at the D line at 25 °C D25 : -173.4 (c = 1.0, CH2Cl2).

[0212] 2. Determination of ee value by high performance liquid chromatography analysis: Chiral column Daicel AD column; 20% i-PrOH in hexanes; 1.0 mL / min; retention time: 14.5 min (major), 10.1 min (minor). The calculated result is 94% ee.

[0213] 3. 1H NMR and 13C NMR of nuclear magnetic resonance analysis:

[0214] 1 H NMR (400 MHz, CDCl3) δ 8.07 - 8.05 (m, 2H), 7.75 - 7.72 (m, 2H), 7.51 (s, 1H), 7.22 - 7.11 (m, 7H), 7.02 - 6.96 (m, 3H), 6.89 (d, J = 2.4 Hz, 1H), 6.82 - 6.80 (m, 1H), 6.75 - 6.74 (m, 2H), 5.11 (s, 1H), 3.60 (s, 3H) ppm.

[0215] 13 C NMR (101 MHz, CDCl3) δ 160.0, 154.3, 141.0, 140.8, 133.3, 133.2, 131.0, 129.9, 129.1, 129.0, 127.7, 125.9, 123.5, 123.0, 121.1, 120.3, 119.4, 117.9, 114.6, 113.1, 110.5, 105.5, 60.5, 55.2 ppm.

[0216] 4. High resolution mass spectrometry: HRMS (CI+) Calcd for C 30 H 22 NO2 - [M - H] - : 428.1656, Found: 428.1644.

[0217] It can be seen from this result that its theoretical mass is 428.1656, while the observed value of the peak found in the actual mass spectrum is 428.1644; combined with nuclear magnetic resonance analysis, the product structure can be determined to be the product of this example.

[0218] Example 13

[0219] A chiral naphthalene compound Using R 1 as hydrogen, R 28-(Hydroxy(aryl)methyl)naphthalen-2-ol with 2-methoxy and R 6 Using carbazole with hydrogen as the reaction raw material and reacting with a chiral phosphoric acid catalyst, the preparation steps include:

[0220] Dissolve 8-(hydroxy(2-methoxyphenyl)methyl)naphthalen-2-ol (84.0 mg, 0.30 mmol), carbazole (75.2 mg, 0.45 mmol), chiral phosphoric acid (13.5 mg, 0.015 mmol) and molecular sieve (30 mg) in dichloromethane (3 mL). React at room temperature for 3 hours. Filter the reaction solution through silica gel, wash with diethyl ether, concentrate and then perform silica gel column chromatography to obtain 116.3 mg of solid product. The calculated yield is 90%, and the measured ee value is 94%. The reaction equation is as follows:

[0221]

[0222] Analyze the obtained solid product. The analysis methods include measuring the specific rotation, determining the ee value by high performance liquid chromatography analysis, nuclear magnetic resonance, and high resolution mass spectrometry. Among them, the test analysis is as follows:

[0223] 1. Specific rotation [α] measured at the D line at 25 °C D 25 : -240.6 (c = 1.0, CH2Cl2).

[0224] 2. Determining the ee value by high performance liquid chromatography analysis: Chiral column Daicel AD column; 20% i-PrOH in hexanes; flow rate: 1.0 mL / min; retention time: 5.4 min (major), 7.1 min (minor). The calculated result is 94% ee.

[0225] 3. 1H NMR and 13C NMR analysis of nuclear magnetic resonance:

[0226] 1 H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.0 Hz, 2H), 7.82 (s, 1H), 7.75 (t, J = 9.6 Hz, 2H), 7.31 - 7.27 (m, 1H), 7.24 - 7.19 (m, 2H), 7.17 - 7.14 (m, 4H), 6.99 - 6.91 (m, 3H), 6.86 (d, J = 2.4 Hz, 1H), 6.79 (t, J = 7.2 Hz, 1H), 4.95 (s, 1H), 3.62 (s, 3H) ppm.

[0227] 1313C NMR (100 MHz, CDCl3) δ 157.2, 153.8, 141.0, 133.2, 133.0, 130.8, 129.3, 129.2, 129.1, 128.7, 127.5, 127.1, 125.6, 123.3, 122.9, 120.7, 120.0, 119.0, 117.6, 110.8, 110.3, 105.6, 55.6, 55.2 ppm.

[0228] 4. High-resolution mass spectrometry: HRMS (CI+) Calcd for C 30 H 22 NO2 - [M-H] - : 428.1656, Found: 428.1653.

[0229] It can be seen from this result that its theoretical mass is 428.1656, while the observed value of the peak found in the actual mass spectrometry is 428.1653; combined with nuclear magnetic resonance analysis, the product structure can be determined to be the product of this example.

[0230] Example 14

[0231] A chiral naphthalene compound Using R 1 being hydrogen, R 2 being 4-methoxy, 8-(hydroxy(aryl)methyl)naphthalen-2-ol and R 6 being hydrogen, carbazole as reaction raw materials, reacting with a chiral phosphoric acid catalyst, and its preparation steps include:

[0232] Dissolve 8-(hydroxy(4-methoxyphenyl)methyl)naphthalen-2-ol (84.0 mg, 0.30 mmol), carbazole (75.2 mg, 0.45 mmol), chiral phosphoric acid (13.5 mg, 0.015 mmol) and molecular sieve (30 mg) in dichloromethane (3 mL). React at room temperature for 2 hours. Filter the reaction solution through silica gel, wash with diethyl ether, concentrate, and obtain 132.1 mg of solid product by silica gel column chromatography. The calculated yield is 99%, and the measured ee value is 97%. The reaction equation is as follows:

[0233]

[0234] Analyze the obtained solid product, and the analysis methods include measuring the specific rotation, determining the ee value by high-performance liquid chromatography analysis, nuclear magnetic resonance, and high-resolution mass spectrometry. Among them, the test analysis is as follows:

[0235] 1. Specific rotation [α] measured at the D line at 25 °C D25 : -73.8 (c = 1.0, CH2Cl2).

[0236] 2. Determination of ee value by high performance liquid chromatography: Chiral column Daicel AD column; 20% i-PrOH in hexanes; 1.0 mL / min; retention time: 9.4 min (major), 21.1 min (minor). The calculated result is 97% ee.

[0237] 3. 1H NMR and 13C NMR for nuclear magnetic resonance analysis:

[0238] 1 H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 6.4 Hz, 2H), 7.71 (d, J = 8.0 Hz, 2H), 7.48 (s, 1H), 7.13 - 7.09 (m, 6H), 7.02 - 6.93 (m, 6H), 6.73 (d, J = 7.6 Hz, 2H), 5.38 (s, 1H), 3.66 (s, 3H) ppm.

[0239] 13 C NMR (100 MHz, CDCl3) δ 159.2, 154.2, 141.0, 133.5, 133.0, 131.0, 129.9, 129.1, 128.8, 127.2, 125.8, 123.5, 123.1, 120.2, 119.3 (2C), 117.9, 114.2, 110.6, 105.7, 60.0, 55.3 ppm.

[0240] 4. High resolution mass spectrometry: HRMS (CI+) Calcd for C 30 H 22 NO2 - [M - H] - : 428.1656, Found: 428.1646.

[0241] It can be seen from this result that the theoretical mass is 428.1656, while the observed value of the peak found in the actual mass spectrum is 428.1646; combined with nuclear magnetic resonance analysis, the product structure can be determined to be the product of this example.

[0242] Example 15

[0243] A chiral naphthalene compound Using R 1 is hydrogen, R 2 is 4 - methylthio, 8 - (hydroxy(aryl)methyl)naphthalen - 2 - ol and R 6Using carbazole with hydrogen as the reaction raw material and carrying out the reaction with a chiral phosphoric acid catalyst, its preparation steps include:

[0244] Dissolve 8-(hydroxy(4-methylthiophenyl)methyl)naphthalen-2-ol (88.9 mg, 0.30 mmol), carbazole (75.2 mg, 0.45 mmol), chiral phosphoric acid (13.5 mg, 0.015 mmol) and molecular sieve (30 mg) in dichloromethane (3 mL). React at room temperature for 3 hours. Filter the reaction solution through silica gel, wash with diethyl ether, concentrate, and obtain 136.6 mg of solid product by silica gel column chromatography. The calculated yield is 99%, and the measured ee value is 96%. The reaction equation is as follows:

[0245]

[0246] Analyze the obtained solid product. The analysis methods include measuring the specific rotation, determining the ee value by high-performance liquid chromatography analysis, nuclear magnetic resonance, and high-resolution mass spectrometry. Among them, the test analysis is as follows:

[0247] 1. Specific rotation [α] measured at the D line at 25 °C D 25 : -150.6 (c = 1.0, CH2Cl2).

[0248] 2. Determining the ee value by high-performance liquid chromatography analysis: Chiral column Daicel AD column; 20% i-PrOH in hexanes; 1.0 mL / min; retention time: 9.1 min (major), 17.2 min (minor). The calculated result is 96% ee.

[0249] 3. 1H NMR and 13C NMR of nuclear magnetic resonance analysis:

[0250] 1 H NMR (400 MHz, CDCl3) δ 8.08 - 8.05 (m, 2H), 7.75 (d, J = 8.8 Hz, 2H), 7.50 (s, 1H), 7.22 - 7.10 (m, 8H), 7.05 - 6.98 (m, 5H), 6.90 (d, J = 2.0 Hz, 1H), 5.11 (s, 1H), 2.39 (s, 3H) ppm.

[0251] 1313C NMR (101 MHz, CDCl3) δ 154.2, 140.9, 138.4, 135.7, 133.1, 131.1, 129.2, 129.1 (2C), 129.0, 127.5, 126.6, 125.9, 123.6, 123.1, 120.3, 119.4, 117.9, 110.5, 105.6, 60.1, 15.6 ppm.

[0252] 4. High-resolution mass spectrometry: HRMS (CI+) Calcd for C 30 H 22 NOS - [M - H] - : 444.1428, Found: 444.1419.

[0253] It can be seen from this result that its theoretical mass is 444.1428, while the observed value of the peak found in the actual mass spectrum is 444.1419; combined with nuclear magnetic resonance analysis, the product structure can be determined to be the product of this example.

[0254] Example 16

[0255] A chiral naphthalene compound Using R 9 being hydrogen, R 8 being 4-methoxy, R 7 being 1-adamantanecarbonyl of (7-aminonaphthalen-1-yl)(aryl)methanol and R 6 being hydrogen of carbazole as reaction raw materials, reacting with a chiral phosphoric acid catalyst, and its preparation steps include:

[0256] Dissolve N-(8-(hydroxy(4-methoxyphenyl)methyl)naphthalen-2-yl)-1-adamantanecarboxamide (132.5 mg, 0.30 mmol), carbazole (75.2 mg, 0.45 mmol), chiral phosphoric acid (27.0 mg, 0.03 mmol) and molecular sieve (30 mg) in dichloromethane (3 mL). React at room temperature for 96 hours. Filter the reaction solution through silica gel, wash with diethyl ether, concentrate and then perform silica gel column chromatography to obtain 144.6 mg of solid product, with a calculated yield of 82% and an ee value of 93% measured. The reaction equation is as follows:

[0257]

[0258] Analyze the obtained solid product, and the analysis methods include measuring the specific rotation, determining the ee value by high-performance liquid chromatography analysis, nuclear magnetic resonance, and high-resolution mass spectrometry. Among them, the test analysis is as follows:

[0259] 1. Specific rotation [α] measured for line D at 25 °C D 25 : +103.8 (c = 1.0, CH2Cl2).

[0260] 2. Determination of ee value by high performance liquid chromatography analysis: Chiral column Daicel IC column; 10% i-PrOH in hexanes; 1.0 mL / min; retention time: 13.6 min (major), 14.9 min (minor). The calculated result is 93% ee.

[0261] 3. 1H NMR and 13C NMR spectra for nuclear magnetic resonance analysis:

[0262] 1 H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 7.2 Hz, 2H), 7.83 - 7.78 (m, 2H), 7.72 (d, J = 8.0 Hz, 1H), 7.67 (m, 1H), 7.64 (d, J = 0.8 Hz, 1H), 7.24 - 7.15 (m, 7H), 7.11 - 7.04 (m, 4H), 6.81 - 6.79 (m, 2H), 3.74 (s, 3H), 2.06 (s, 3H), 1.85 (d, J = 2.4 Hz, 6H), 1.72 (q, J = 12.4 Hz, 6H) ppm.

[0263] 13 C NMR (100 MHz, CDCl3) δ 176.2, 159.3, 141.0, 136.6, 134.7, 132.0, 131.0, 130.7,

[0264] 130.1, 129.9, 128.5, 126.8, 125.8, 124.4, 123.5, 120.6, 120.1, 119.3, 114.1, 112.4, 110.7, 59.6, 55.3, 41.5, 39.2, 36.5, 28.2 ppm.

[0265] 4. High resolution mass spectrometry: HRMS (CI+) Calcd for C 41 H 38 N2NaO2 + [M+Na] + : 613.2825, Found: 613.2833.

[0266] It can be seen from this result that its theoretical mass is 613.2825, while the observed value of the peak found in the actual mass spectrum is 613.2833; combined with nuclear magnetic resonance analysis, the product structure can be determined to be the product of this example.

[0267] Example 17

[0268] A chiral naphthalene compound Using R 9 is hydrogen, R 8 is 4-methoxy, R 7 is 1-adamantanecarbonyl of (7-aminonaphthalen-1-yl)(aryl)methanol and R 6 is 3-tert-butyl carbazole as reaction raw materials, and react with a chiral phosphoric acid catalyst. Its preparation steps include:

[0269] Dissolve N-(8-(hydroxy(4-methoxyphenyl)methyl)naphthalen-2-yl)adamantane-1-carboxamide (132.5 mg, 0.30 mmol), 3-tert-butyl carbazole (100.5 mg, 0.45 mmol), chiral phosphoric acid (27.0 mg, 0.03 mmol) and molecular sieve (30 mg) in dichloromethane (3 mL). React at room temperature for 120 hours. Filter the reaction solution through silica gel, wash with diethyl ether, concentrate and perform silica gel column chromatography to obtain 175.5 mg of solid product. The calculated yield is 90%, and the measured ee value is 90%. The reaction equation is as follows:

[0270]

[0271] Analyze the obtained solid product. The analysis methods include measuring specific rotation, determining the ee value by high performance liquid chromatography analysis, nuclear magnetic resonance and high resolution mass spectrometry. Among them, the test analysis is as follows:

[0272] 1. Specific rotation [α] measured at 25 °C with D line D 25 :+26.0 (c = 1.0, CH2Cl2).

[0273] 2. Determining the ee value by high performance liquid chromatography analysis: Chiral column Daicel IC column; 5% i-PrOH in hexanes; 1.0 mL / min; retention time: 17.0 min (major), 21.5 min (minor). The calculated result is 90% ee.

[0274] 3. 1H NMR and 13C NMR analysis

[0275] 11H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 7.2 Hz, 2H), 7.82 (dd, J1 = 8.8 Hz, J2 = 1.6 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 6.4 Hz, 2H), 7.65 (s, 1H), 7.28 (dd, J1 = 8.8 Hz, J2 = 2.0 Hz, 1H), 7.24 (s, 1H), 7.22 - 7.12 (m, 4H), 7.09 - 7.03 (m, 3H), 6.94 (d, J = 8.8 Hz, 1H), 6.77 (d, J = 8.8 Hz, 2H), 3.70 (s, 3H), 2.04 (s, 3H), 1.85 (d, J = 2.4 Hz, 6H), 1.70 (q, J = 11.6 Hz, 6H), 1.39 (s, 9H) ppm.

[0276] 13 13C NMR (100 MHz, CDCl3) δ 176.2, 159.2, 142.1, 141.2, 139.1, 136.6, 134.9, 132.0, 131.0, 130.9, 130.1, 129.8, 128.5, 126.9, 125.4, 124.4, 123.8, 123.7, 123.1, 120.7, 119.9, 119.0, 116.2, 114.1, 112.4, 110.5, 110.2, 59.4, 55.3, 41.5, 39.2, 36.5, 34.6, 32.0, 28.2 ppm.

[0277] 4. High-resolution mass spectrometry: HRMS (CI+) Calcd for C 45 H 46 N2NaO2 + [M + Na] + : 669.3451, Found: 669.3459.

[0278] It can be seen from the results that its theoretical mass is 669.3451, while the observed value of the peak found in the actual mass spectrometry is 669.3459; combined with nuclear magnetic resonance analysis, the product structure can be determined to be the product of this example.

[0279] Example 18

[0280] A chiral naphthalene compound Using R 9 being hydrogen, R 8 being 4-methoxy, R 7 being 1-adamantanoyl of (7-aminonaphthalen-1-yl)(aryl)methanol and R 3 being methyl, R 4is methyl, R 5 Using indole where R is hydrogen as the reaction raw material and carrying out the reaction with a chiral phosphoric acid catalyst, the preparation steps include:

[0281] Dissolve N-(8-(hydroxy(4-methoxyphenyl)methyl)naphthalen-2-yl)adamantane-1-carboxamide (132.5 mg, 0.30 mmol), 2,3-dimethylindole (65.3 mg, 0.45 mmol), chiral phosphoric acid (27.0 mg, 0.03 mmol) and molecular sieve (30 mg) in dichloromethane (3 mL). React at room temperature for 96 hours. Filter the reaction solution through silica gel, wash with diethyl ether, concentrate and then perform silica gel column chromatography to obtain 133.1 mg of solid product. The calculated yield is 78%, and the measured ee value is 95%. The reaction equation is as follows:

[0282]

[0283] Analyze the obtained solid product. The analysis methods include measuring the specific rotation, determining the ee value by high performance liquid chromatography analysis, nuclear magnetic resonance, and high resolution mass spectrometry. Among them, the test analysis is as follows:

[0284] 1. Specific rotation [α] measured at the D line at 25 °C D 25 : +52.4 (c = 1.0, CH2Cl2).

[0285] 2. Determining the ee value by high performance liquid chromatography analysis: Chiral column Daicel IC column; 5% i-PrOH in hexanes; 1.0 mL / min; retention time: 17.9 min (major), 20.7 min (minor). The calculated result is 95% ee.

[0286] 3. 1H NMR and 13C NMR spectra for nuclear magnetic resonance analysis:

[0287] 1 H NMR (400 MHz, CDCl3) δ 7.82 - 7.68 (m, 4H), 7.48 (d, J = 7.6 Hz, 1H), 7.39 (s, 1H), 7.27 - 7.22 (m, 2H), 7.01 - 6.95 (m, 4H), 6.85 - 6.79 (m, 3H), 6.65 (d, J = 8.4 Hz, 1H), 3.77 (s, 3H), 2.25 (s, 3H), 2.18 (s, 3H), 2.08 (s, 3H), 1.91 (d, J = 2.4 Hz, 6H), 1.74 (q, J = 12.4 Hz, 6H) ppm.

[0288] 1313C NMR (100 MHz, CDCl3) δ 176.2, 159.0, 136.9, 136.3, 135.5, 133.8, 132.0, 131.8, 130.9, 130.1, 129.7, 129.3, 128.3, 127.2, 124.5, 120.6, 120.5, 118.6, 117.9, 114.0, 112.8, 111.0, 107.9, 59.8, 55.3, 41.6, 39.3, 36.5, 28.2, 11.6, 9.1 ppm.

[0289] 4. High-resolution mass spectrometry: HRMS (CI+) Calcd for C 39 H 40 N2NaO2 + [M+Na] + : 591.2982, Found: 591.2989.

[0290] It can be seen from this result that its theoretical mass is 591.2982, while the observed value of the peak found in the actual mass spectrometry is 591.2989; combined with nuclear magnetic resonance analysis, the product structure can be determined to be the product of this example.

[0291] Example 19

[0292] A chiral naphthalene compound Using R 9 being hydrogen, R 8 being 4-methoxy, R 7 being 1-adamantanoyl of (7-aminonaphthalen-1-yl)(aryl)methanol and R 3 being methyl, R 4 being phenyl, R 5 being hydrogen of indole as reaction raw materials, reacting with a chiral phosphoric acid catalyst, and its preparation steps include:

[0293] Dissolve N-(8-(hydroxy(4-methoxyphenyl)methyl)naphthalen-2-yl)adamantane-1-carboxamide (132.5 mg, 0.30 mmol), 2-phenyl-3-methylindole (93.3 mg, 0.45 mmol), chiral phosphoric acid (27.0 mg, 0.03 mmol) and molecular sieve (30 mg) in dichloromethane (3 mL). React at room temperature for 96 hours. Filter the reaction solution through silica gel, wash with ether, concentrate, and obtain 124.6 mg of solid product by silica gel column chromatography. The calculated yield is 66%, and the measured ee value is 98%. The reaction equation is as follows:

[0294]

[0295] The obtained solid product was analyzed by measuring the specific rotation, determining the ee value by high performance liquid chromatography analysis, nuclear magnetic resonance and high resolution mass spectrometry. Among them, the test analysis is as follows:

[0296] 1. Specific rotation [α] measured at 25 °C with a D line D 25 : +100.2 (c = 1.0, CH2Cl2).

[0297] 2. Determination of the ee value by high performance liquid chromatography analysis: Chiral column Daicel IC column; 10% i-PrOH in hexanes; 1.0 mL / min; retention time: 17.4 min (major), 21.5 min (minor). The calculated result is 98% ee.

[0298] 3. 1H NMR and 13C NMR analysis for nuclear magnetic resonance analysis:

[0299] 1 H NMR (400 MHz, CDCl3) δ 8.03 (dd, J1 = 8.8 Hz, J2 = 1.2 Hz, 1H), 7.76 (d, J = 9.2 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.29 - 7.21 (m, 8H), 7.10 (d, J = 14.8 Hz, 2H), 7.02 (t, J = 7.6 Hz, 1H), 6.93 (d, J = 8.0 Hz, 2H), 6.86 (t, J = 8.0 Hz, 1H), 6.77 (t, J = 9.6 Hz, 3H), 3.74 (s, 3H), 2.27 (s, 3H), 2.10 (s, 3H), 1.93 (s, 6H), 1.80 - 1.72 (m, 6H) ppm.

[0300] 13 C NMR (101 MHz, CDCl3) δ 176.0, 158.8, 138.5, 136.8, 136.5, 135.5, 132.6, 132.5, 131.8, 131.0 (2C), 130.8, 129.64, 129.60, 129.5, 128.4, 128.1, 127.9, 124.2, 121.8, 120.7, 119.1, 118.8, 113.9, 112.8, 112.4, 109.9, 60.6, 55.3, 41.5, 39.3, 36.5, 28.2, 9.7 ppm.

[0301] 4. High resolution mass spectrometry: HRMS (CI+) Calcd for C 44 H 42N2NaO2 + [M+Na] + :653.3138, Found:653.3149.

[0302] It can be seen from this result that its theoretical mass is 653.3138, while the observed value of the peak found in the actual mass spectrometry is 653.3149; combined with nuclear magnetic resonance analysis, the product structure can be determined to be the product of this embodiment.

[0303] The above are only the preferred embodiments of the present application and are not intended to limit the present application. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present application shall be included within the protection scope of the present application.

Claims

1. A preparation method of a novel naphthoquinone intermediate, characterized in that, It includes the following steps: The compound A is dehydrated using a chiral phosphoric acid catalyst to obtain a novel naphthoquinone intermediate; the general structural formula of the compound A is The general structural formula of the novel naphthoquinone intermediate is wherein, R 1' , R 2' are each independently selected from one of hydrogen, alkyl, and ether, X is O or NR 3' , R 3' is one of hydrogen and acyl; the chiral phosphoric acid catalyst is selected from The substituents at the 3-position and 3'-position of the binaphthyl skeleton of the chiral phosphoric acid catalyst are 2,4,6-tricyclopentylphenyl.

2. The preparation method of the novel naphthoquinone intermediate according to claim 1, characterized in that, The dosage of the chiral phosphoric acid catalyst is 5-10 mol% of the molar dosage of compound A; And / or, the dehydration treatment step includes: after dissolving and dispersing compound A, the chiral phosphoric acid catalyst, and molecular sieve in a first organic solvent, performing a mixing treatment at a temperature of 0-25 °C to dehydrate compound A by one molecule to obtain the novel naphthoquinone intermediate.

3. The preparation method of the novel naphthoquinone intermediate according to claim 2, characterized in that, The first organic solvent includes one of dichloromethane, dichloroethane, and chlorobenzene; and / or, said molecule is selected from molecular sieve; And / or, in the mixing treatment system, the concentration of the molecular sieve is 80-120 mg / mmol; And / or, in the mixing treatment system, the concentration of compound A is 0.050-0.1 mol / L.

4. A novel naphthoquinone intermediate prepared by the method according to any one of claims 1 to 3, characterized in that, The general structural formula of the novel naphthoquinone intermediate is wherein, R 1' , R 2' are each independently selected from one of hydrogen, alkyl, and ether, X is O or NR 3' , and R 3' is one of hydrogen and acyl group.

5. A method for preparing a chiral naphthalene compound, characterized in that, It includes the following steps: Dissolve compound A, chiral phosphoric acid catalyst, and nucleophile in a second organic solvent for mixing reaction. After in-situ generating a novel naphthoquinone intermediate, perform nucleophilic substitution to obtain a chiral naphthalene compound; the general structural formula of the compound A is The general structural formula of the chiral naphthalene compound is wherein, R 1' , R 2' are each independently selected from one of hydrogen, alkyl, and ether, X is O or NR 3' , R 3' is one of hydrogen and acyl group, and R 4' is a nucleophilic group; The nucleophile includes at least one of; wherein, R 3 , R 4 are each independently selected from one of alkyl and aryl, and R 5 , R 6 are each independently selected from one of alkyl, aryl, halogen, and ether; The chiral phosphoric acid catalyst is selected from The substituents at the 3-position and 3'-position of the binaphthyl skeleton of the chiral phosphoric acid catalyst are 2,4,6-tricyclopentylphenyl.

6. The method for preparing the chiral naphthalene compound according to claim 5, characterized in that, The compound A is selected from at least one of ; wherein, R 1 , R 2 , R 8 , R 9 are each independently selected from one of hydrogen, alkyl, and ether, and R 7 is selected from one of acyl groups; And / or, the temperature condition of the mixing reaction is 0-25 °C; And / or, a molecular sieve with a concentration of 80-120 mg / mmol is further added to the mixing reaction system; And / or, the dosage of the chiral phosphoric acid catalyst is 5-10 mol% of the molar dosage of compound A; And / or, the second organic solvent includes one of dichloromethane, dichloroethane, and chlorobenzene.

7. The method for preparing the chiral naphthalene compound according to claim 6, wherein The chiral naphthalene compound includes at least one of 8. The method for preparing the chiral naphthalene compound according to claim 7, characterized in that, The chiral naphthalene compound includes at least one of 9. A chiral naphthalene compound prepared by the method according to any one of claims 5 to 8, characterized in that, The chiral naphthalene compounds include at least one of

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