Optically active amine derivative as well as asymmetric alkylation synthesis method and application thereof

Abstract

The invention belongs to the field of medicinal chemistry, and relates to an optically active amine derivative as well as an asymmetric alkylation synthesis method and application thereof. According to the free radical type asymmetric C (sp3)-H alkylation synthesis method, methylation or ethylation modification is carried out on ortho-position C (sp3)-H bonds of substrate nitrogen atoms by adopting a light / nickel concerted catalysis system, taking peroxide as an alkyl free radical source and taking hexafluoroisopropanol (HFIP) as a solvent, a quaternary carbon three-dimensional center is successfully constructed, and thus a series of optically active amine derivatives are efficiently constructed. The optically active amine derivative has a structure as shown in the following general formula (I): # imgabs0 # dotted line represents bond connection or no bond connection; each Z is independently selected from CR1 or N; r is selected from methyl or ethyl; y1 is selected from H or # imgabs1 # or # imgabs2 #; Y2 is selected from H or # imgabs3 #; Y3 is selected from H or # imgabs4 # or # imgabs5 #; X is selected from O, S or NH; # imgabs6 # represents a connection site, and C * represents chiral carbon and comprises R and S configurations.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry and relates to an optically active amine derivative and an asymmetric alkylation synthesis method and application thereof. Background Art

[0002] Benzenesulfonates are a class of structural skeletons containing multiple heteroatoms, which are present in many biologically significant natural products, drugs, and agricultural preparations, such as immunostimulants, aldose reductase inhibitors, antibacterial agents, and anti-inflammatory drugs. Representative examples include HIV-1 inhibitory enzymes 1, aldose reductase 2, metaxalone for treating muscle spasms 3, and non-steroidal anti-inflammatory drugs Celebrex 4. In addition, benzenesulfonate derivatives have important applications in the field of organic chemistry, such as chiral auxiliary agents 5, fluorination reagents 6, and directed metallization reagents. In addition, benzenesulfonates can be converted into important structural units such as α-quaternary carbon amines and α-quaternary carbon amino acids through simple reactions. Therefore, the multifunctional modification of benzenesulfonates has become a research hotspot in drug development and organic synthesis.

[0003]

[0004] Methyl groups occupy a unique position in medicinal chemistry and have an important impact on pharmacological properties. Methylation of the CH bond can significantly change the conformation of the molecule, thereby significantly improving the efficacy, changing the drug metabolism and pharmacokinetic properties. For example, after the introduction of a methyl group at the benzyl position of the lead compound MK-0524, the selectivity for TP receptors increased by 87 times. When the first methyl group was introduced at the benzyl position of the S1P1 receptor antagonist 8, its IC 50 The value was reduced from 4270nM to 4.3nM, and the activity was increased by nearly 1000 times. After the second methyl group was introduced on another benzene ring, its activity could be increased by 2135 times. Compound 9 is easily oxidized and metabolized in vivo to produce 3,5-di(trifluoromethyl)benzoic acid and become inactivated. The clinical drug aprepitant formed by the introduction of a methyl group at its benzyl position can effectively block this metabolic site, making the peripheral and central effects last longer. Therefore, the introduction of a methyl group into the benzylamine or benzyl alcohol skeleton is an effective drug modification strategy.

[0005]

[0006] C(sp 3 )-H bond is one of the most common chemical bonds. However, due to its large bond energy (414KJ / mol) and low polarity, its efficient breaking and functionalization face many difficulties. 3 )-H methylation methods have been developed, but they are often limited by strong bases, multi-step reactions, ultra-low temperature conditions, and poor universality. Although alcohols, peroxides, sulfinates and other reagents are used as methyl radical precursors, C(sp3 )-H methylation has been reported in a few cases, but asymmetric C(sp 3 )-H methylation transformation is still one of the difficulties in the field of organic chemistry. It is worth noting that the stereo-convergent C(sp 3 )-H methylation to construct a quaternary carbon chiral center has not been reported so far.

[0007] Therefore, it is necessary to develop a three-dimensional convergence C (sp 3 )-H methylation method has important scientific research significance. Summary of the invention

[0008] In view of this, the object of the present invention is to provide an optically active amine derivative and its application. The present invention also provides a free radical type stereo convergent C (sp 3 The invention discloses a method for synthesizing a )-H asymmetric alkylation (methylation and ethylation), which has the advantages of high efficiency, strong practicability, mild conditions, excellent enantioselectivity, and avoids the use of harsh conditions such as strong acid, strong base, high temperature, and methyl metal reagents and noble metal salts. In addition, the invention also provides an application of the asymmetric alkylation synthesis method in the field of late-stage derivatization and modification of natural products or candidate drugs.

[0009] In order to achieve the above object, the present invention provides the following technical solutions:

[0010] In a first aspect of the present invention, an optically active amine derivative is provided, wherein the optically active amine derivative has a structure shown in the following general formula (I):

[0011]

[0012] Dashed lines indicate bonding or non-bonding;

[0013] Each Z is independently selected from CR 1 or N; R is selected from methyl or ethyl;

[0014] Y 1 Select from H or

[0015] Y 2 Select from H or

[0016] Y 3 Select from H or

[0017] X is selected from O, S or NH; represents the connection site; C* represents chiral carbon, including R and S configurations;

[0018] Each of the R 1are independently selected from H, halogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 alkoxy, cyano, substituted alkynyl, substituted alkenyl, substituted or unsubstituted aryl having 5 to 40 ring atoms, substituted or unsubstituted heteroaryl having 5 to 40 ring atoms; the adjacent R 1 They may or may not form a ring;

[0019] The R 2 is selected from substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 ester, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 amide, substituted or unsubstituted C1-C10 sulfonamide, substituted alkynyl, substituted alkenyl, substituted or unsubstituted aryl having 5 to 40 ring atoms, or one of the following structures:

[0020]

[0021] The R 3 is selected from substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 acyloxy, substituted or unsubstituted C1-C10 alkoxy, and substituted or unsubstituted C1-C10 amino.

[0022] In some embodiments, the optically active amine derivatives include 3-alkyl-3-quaternary carbon benzsulfonam derivatives, and the chemical structure of the 3-alkyl-3-quaternary carbon benzsulfonam derivatives is shown in the following formula (II) or (III) or (IV):

[0023]

[0024] Z are independently selected from CR 1 or N; X is selected from O, S or NH; R is selected from methyl or ethyl;

[0025] R 1 As shown in claim 1, comprising H, 5-fluoro, 6-fluoro, 7-fluoro, 5-chloro, 6-chloro, 7-chloro, 5-phenyl, 5-p-methoxyphenyl, 5-p-chlorophenyl, 5-p-cyanophenyl, 5-trifluoromethoxy, 5-trifluoromethyl, 5-methyl, 5-ethyl, 5-propyl, 5-butyl, 5-tert-butyl, 5-methoxy, 5-ethoxy, 5-cyano, 5-(2-phenyl)alkynyl, 5-(2-phenyl)alkenyl, 1-naphthyl, 2-naphthyl or benzofuran;

[0026] R 2 As shown in claim 1, it includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, phenyl, p-methoxyphenyl or one of the following structures:

[0027]

[0028] In some embodiments, the optically active amine derivatives include 2-aminoethylpyridine derivatives, and the chemical structure of the 2-aminoethylpyridine derivatives is shown in the following formula (V):

[0029]

[0030] Z are independently selected from CR 1 or N;

[0031] R 1 As shown in claim 1, comprising H, 4-chloro, 3-chloro, 5-chloro, 6-chloro, 6-fluoro, 3-bromo, 5-trifluoromethyl, 4-methoxy, 6-methoxy, 4-phenyl, 4-(4-cyano)phenyl, 4-(4-tert-butyl)phenyl, 4-(4-butyl)phenyl, 4-(4-methoxycarbonyl)phenyl, 4-(4-phenylaminocarbonyl)phenyl, 2-quinoline or 3-isoquinoline;

[0032] R 3 As shown in claim 1, it includes methyl, tert-butyl, tert-butyloxycarbonyl, 1,1-dimethylbutyl, and 1,1-dimethyl-4-methoxycarbonylbutyl.

[0033] The second aspect of the present invention provides the use of the optically active amine derivatives in antiviral, anti-inflammatory, anti-tumor and other drugs.

[0034] The third aspect of the present invention provides a free radical type C (sp 3 )-H asymmetric alkylation synthesis method, characterized in that the synthesis route of the method is as follows:

[0035]

[0036] Among them, the dashed line, Z, R, C*, Y 1 , Y 2 , Y 3 The definition is the same as that of claims 1 to 3.

[0037] The method comprises the following steps:

[0038] In an argon or nitrogen atmosphere, a nickel salt catalyst, a chiral ligand, a photocatalyst, an amine substrate, an additive and a solvent are mixed to prepare a first reaction mixture; a peroxide alkyl source is added to the first reaction mixture to prepare a second reaction mixture; and the second reaction mixture is subjected to a photocatalytic reaction.

[0039] In some embodiments, the nickel salt includes one or more of ethylene glycol dimethyl ether nickel bromide, ethylene glycol dimethyl ether nickel chloride, bis(triphenylphosphine)nickel chloride, bis(triphenylphosphine)nickel bromide, tetrapyridine nickel chloride, nickel chloride, nickel bromide, nickel iodide, nickel acetylacetonate, nickel trifluoromethanesulfonate, bis-(1,5-cyclooctadiene)nickel, and nickel acetate.

[0040] In some embodiments, the chiral ligand includes (3aS, 3a'S, 8aR, 8a'R)-2,2'-isopropylidenebis(3a,8a-dihydro-8H-indeno[1,2-d]oxazole), (3aR, 3a'R, 8aS, 8a'S)-2,2'-isopropylidenebis(3a,8a-dihydro-8H-indeno[1,2-d]oxazole), (3aS, 3a'S, 8aR, 8a'R)-2,2'-cyclopentylenebis(3a,8a-dihydro-8H-indeno[1,2-d]oxazole ), (3aR, 3a'R, 8aS, 8a'S)-2,2'-cyclopentylenebis(3a,8a-dihydro-8H-indeno[1,2-d]oxazole), (3aS, 3a'S, 8aR, 8a'R)-2,2'-cyclopropylenebis(3a,8a-dihydro-8H-indeno[1,2-d]oxazole), (3aR, 3a'R, 8aS, 8a'S)-2,2'-cyclopropylenebis(3a,8a-dihydro-8H-indeno[1,2-d]oxazole), (3aS, 3a'S, 8aR ,8a'R)-2,2'-(1,3-diarylpropane-2,2-diyl)bis(3a,8a-dihydro-8H-indeno[1,2-d]oxazole), (3aR,3a'R,8aS,8a'S)-2,2'-(1,3-diarylpropane-2,2-diyl)bis(3a,8a-dihydro-8H-indeno[1,2-d]oxazole), (4S,4'S)-2,2'-cyclopentylidenebis[4,5-dihydro-4-phenyloxazole], (4R,4'R)-2,2'-cyclopentylidenebis[4 ,5-dihydro-4-phenyloxazole], (4R,4'R)-2,2'-cyclopropylene[4,5-dihydro-4-phenyloxazole] and (4S,4'S)-2,2'-cyclopropylene[4,5-dihydro-4-phenyloxazole] or a combination of more thereof; wherein the aryl group specifically includes phenyl, p-fluorophenyl, p-chlorophenyl, p-methoxyphenyl, p-tert-butylphenyl, o-fluorophenyl, o-chlorophenyl, o-methoxyphenyl, m-fluorophenyl, m-chlorophenyl, m-methoxyphenyl, 3,5-dimethoxyphenyl, 1-naphthyl and 2-naphthyl.

[0041] In some embodiments, the photocatalyst includes [4,4′-di-tert-butyl-2,2′-bipyridine N1, N1′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl N]phenyl-C]iridium(III) hexafluorophosphate.

[0042] In some embodiments, the solvent includes hexafluoroisopropanol or trifluoroethanol.

[0043] In some embodiments, the alkyl source includes one of tert-butyl peroxide, dicumyl peroxide, and di-tert-amyl peroxide.

[0044] In some embodiments, the additive includes sodium tetraphenylborate.

[0045] The general structural formula of the amine substrate to be alkylated is shown in the following formula (VI):

[0046]

[0047] Dashed Line, Z, Y 1 , Y 2 , Y 3 The definition is the same as that of claims 1 to 3.

[0048] In some embodiments, the molar percentage of the nickel salt catalyst and the amine substrate is 5% to 20%.

[0049] In some embodiments, the molar percentage of the photocatalyst and the amine substrate is 0.8% to 1.5%.

[0050] In some embodiments, the molar percentage of the chiral ligand and the amine substrate is 6% to 24%.

[0051] In some embodiments, the molar ratio of the nickel salt catalyst to the chiral ligand is 1:(1.0-1.5).

[0052] In some embodiments, the molar ratio of the nickel salt catalyst to the photocatalyst is (5-20):1.

[0053] In some embodiments, the molar equivalent of the alkyl source to the amine substrate is 2.0 eq. to 12.0 eq.

[0054] In some embodiments, the molar equivalent of the additive to the amine substrate to be alkylated is 0.2 eq. to 1.0 eq.

[0055] In some embodiments, the light source for the photocatalytic reaction is blue light.

[0056] In some embodiments, the reaction temperature of the photocatalytic reaction is -25°C to 30°C.

[0057] In some embodiments, the reaction time of the photocatalytic reaction is 24 hours to 72 hours.

[0058] In some embodiments, the photocatalytic reaction further includes a step of separation using silica gel column chromatography;

[0059] The eluent of the silica gel column chromatography includes a mixed solution of petroleum ether, acetone and dichloromethane or a mixed solution of petroleum ether and ethyl acetate.

[0060] The fourth aspect of the present invention provides a free radical type C (sp 3 Application of )-H asymmetric alkylation synthesis method in the field of late derivatization and modification of natural products or candidate drugs.

[0061] The beneficial effects of the present invention are:

[0062] The invention provides an optically active amine derivative which is easy to synthesize, most of which have a chiral quaternary carbon stereocenter, thereby expanding the application scope of chiral benzsulfonam and 2-aminoethylpyridine candidate drugs in the creation of new drugs.

[0063] The present invention provides an economical and practical free radical type C (sp 3 )-H asymmetric alkylation synthesis method, using a light / nickel synergistic catalytic system, can efficiently construct optically active amine derivatives containing quaternary carbon stereocenters in one step under mild conditions. The preparation method is simple, the conditions are mild, the yield is high, and the enantioselectivity is excellent. In addition, this method combines photocatalysis and nickel catalytic systems to effectively capture highly active methyl radicals and effectively control S H The stereochemistry of process 2 successfully solved the synthetic difficulties of asymmetric methylation reactions.

[0064] Other advantages, objectives and features of the present invention will be described in the following description to some extent, and to some extent, will be obvious to those skilled in the art based on the following examination and study, or can be taught from the practice of the present invention. The objectives and other advantages of the present invention can be realized and obtained through the following description. DETAILED DESCRIPTION

[0065] The following describes the embodiments of the present invention by specific examples, and those skilled in the art can easily understand other advantages and effects of the present invention from the contents disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and the details in this specification can also be modified or changed in various ways based on different viewpoints and applications without departing from the spirit of the present invention. It should be noted that the illustrations provided in the following embodiments only illustrate the basic concept of the present invention in a schematic manner, and the following embodiments and features in the embodiments can be combined with each other without conflict.

[0066] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in the specification of the present invention herein are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0067] Where “including,” “having,” and “comprising” are used herein, it is intended to cover a non-exclusive inclusion, and another component / component may also be added unless explicit limiting terms such as “only,” “consisting of,” etc. are used.

[0068] In the present invention, the terms "first" and "second" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Therefore, the features defined as "first" and "second" may explicitly or implicitly include at least one of the features.

[0069] The words "preferably", "more preferably", "preferably", "better", etc. in the present invention refer to embodiments of the present invention that can provide certain beneficial effects in certain circumstances. However, other embodiments may also be preferred under the same circumstances or other circumstances. In addition, the statement of one or more preferred embodiments does not imply that other embodiments are not applicable, nor is it intended to exclude other embodiments from the scope of the present invention. That is, in the present invention, "preferably", "more preferably", "preferably", "better", etc. are only used to describe implementation methods or examples with better effects, but do not constitute a limitation on the scope of protection of the present invention.

[0070] In the present invention, “further”, “furthermore”, “particularly”, etc. are used for descriptive purposes to indicate differences in content, but should not be construed as limiting the scope of protection of the present invention.

[0071] When a numerical range is disclosed in the present invention, the above range is considered to be continuous and includes the minimum and maximum values ​​of the range, as well as each value between such minimum and maximum values. Further, when the range refers to an integer, each integer between the minimum and maximum values ​​of the range is included. In addition, when multiple ranges are provided to describe features or characteristics, the range can be merged. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all sub-ranges included therein. And only some numerical ranges are specifically disclosed herein. However, any lower limit can be combined with any upper limit to form an unambiguous range; and any lower limit can be combined with other lower limits to form an unambiguous range, and any upper limit can also be combined with any other upper limit to form an unambiguous range. In addition, each individually disclosed point or single value itself can be combined with any other point or single value as a lower limit or upper limit or with other lower limits or upper limits to form an unambiguous range.

[0072] If not otherwise specified, all steps of the present invention may be performed sequentially or randomly. For example, the method includes steps (a) and (b), which means that the method may include steps (a) and (b) performed sequentially, or may include steps (b) and (a) performed sequentially. For example, the method may further include step (c), which means that step (c) may be added to the method in any order, for example, the method may include steps (a), (b) and (c), or may include steps (a), (c) and (b), or may include steps (c), (a) and (b), etc.

[0073] Unless mentioned to the contrary, terms in the singular may include plural forms and should not be construed as being one in number.

[0074] The temperature parameters in the present invention, if not specifically limited, allow for both constant temperature treatment and treatment within a certain temperature range. The constant temperature treatment allows the temperature to fluctuate within the precision range controlled by the instrument.

[0075] The weights of the relevant components mentioned in the embodiments of the present invention description may not only refer to the specific content of each component, but also indicate the weight ratio between the components. Therefore, as long as the content of the relevant components in the embodiments of the present invention description is proportionally enlarged or reduced, it is within the scope disclosed in the embodiments of the present invention description. Specifically, the weights described in the embodiments of the present invention description may be mass units known in the chemical industry such as μg, mg, g, and kg.

[0076] In the present invention, when referring to the unit of the data range, if there is a unit only after the right endpoint, it means that the units of the left endpoint and the right endpoint are the same. For example, 800-850nm means that the units of the left endpoint "800" and the right endpoint "850" are both nm (nanometers).

[0077] In the present invention, "A and B are independently selected from x, y or z" means that A and B are independent events, and event A does not affect the occurrence of event B. Therefore, when A is selected from x, B can be selected from any one of x, y or z; when A is selected from y, B can be selected from any one of x, y or z; when A is selected from z, B can be selected from any one of x, y or z.

[0078] In the present invention, the "number of ring atoms" refers to the number of atoms in the atoms constituting the ring itself of a structural compound (e.g., a monocyclic compound, a condensed ring compound, a cross-linked compound, a carbocyclic compound, a heterocyclic compound) in which atoms are bonded to form a ring. When the ring is substituted with a substituent, the atoms contained in the substituent are not included in the ring atoms. The same is true for the "number of ring atoms" described below unless otherwise specified. For example, the number of ring atoms of a benzene ring is 6, the number of ring atoms of a naphthalene ring is 10, and the number of ring atoms of a thienyl group is 5.

[0079] In the present invention, "alkyl" may represent a linear, branched and / or cyclic alkyl group. The carbon number of the alkyl group may be 1 to 50, 1 to 30, 1 to 20, 1 to 10. A phrase containing this term, for example, "C1-C9 alkyl" means an alkyl group containing 1 to 9 carbon atoms, and each occurrence may be independently C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C7 alkyl, C8 alkyl or C9 alkyl. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, 2-ethylbutyl, 3,3-dimethylbutyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, cyclopentyl, 1-methylpentyl, 3-methylpentyl, 2-ethylpentyl, 4-methyl-2-pentyl, n-octyl, n-hexyl, 1-methylhexyl, 2-ethylhexyl, 2-butylhexyl, cyclohexyl, 1,1-dimethylbutyl, adamantane, and the like.

[0080] The term "alkoxy" refers to a group having an -O-alkyl group, i.e., an alkyl group as defined above connected to a parent core structure via an oxygen atom. Phrases containing the term, suitable examples include, but are not limited to, methoxy (-OMe), ethoxy (-OEt) and tert-butoxy (-OtBu).

[0081] "Aryl or aromatic group" refers to an aromatic hydrocarbon group derived from an aromatic ring compound by removing a hydrogen atom, which may be a monocyclic aromatic group, a condensed aromatic group, or a polycyclic aromatic group. For polycyclic rings, at least one is an aromatic ring system. For example, "substituted or unsubstituted aromatic group having 5 to 40 ring atoms" refers to a substituted or unsubstituted aromatic group containing 5 to 40 ring atoms, preferably an aromatic group having 5 to 30 ring atoms, more preferably an aromatic group having 5 to 18 ring atoms, and particularly preferably an aromatic group having 5 to 14 ring atoms, and the aromatic group may be further substituted; suitable examples include, but are not limited to, benzene, biphenyl, terphenyl, naphthalene, anthracene, fluoranthene, phenanthrene, triphenylene, perylene, tetracene, pyrene, benzopyrene, acenaphthene, fluorene and derivatives thereof. It is understandable that multiple aromatic groups may also be interrupted by short non-aromatic units (e.g. <10% non-H atoms, such as C, N or O atoms), specifically acenaphthene, fluorene, or 9,9-diarylfluorene, triarylamine, diaryl ether systems should also be included in the definition of aromatic groups.

[0082] "Heteroaryl or heteroaromatic group" means that at least one carbon atom on the basis of an aromatic group is replaced by a non-carbon atom, and the non-carbon atom may be a N atom, an O atom, a S atom, etc. For example, "substituted or unsubstituted heteroaryl having 5 to 40 ring atoms" refers to a substituted or unsubstituted heteroaryl containing 5 to 40 ring atoms, preferably a heteroaryl having 5 to 30 ring atoms, more preferably a heteroaryl having 5 to 18 ring atoms, and particularly preferably a heteroaryl having 5 to 14 ring atoms, and the heteroaryl group is optionally further substituted. Suitable examples include, but are not limited to, triazine, pyridine, pyrimidine, imidazole, furan, thiophene, benzofuran, benzothiophene, indole, carbazole, pyrroloimidazole, pyrrolopyrrole, thienopyrrole, thienothiophene, furopyrrole, furanofuran, thienofuran, benzisoxazole, benzisothiazole, benzimidazole, quinoline, isoquinoline, o-naphthylidene, quinoxaline, phenanthridine, primary idine, quinazoline, quinazolinone, dibenzothiophene, dibenzofuran, carbazole and derivatives thereof.

[0083] The reaction process of the present invention is as follows:

[0084]

[0085] Preferably, in some examples, the optically active α-methylamine derivative comprises one of the structures shown below:

[0086]

[0087] The present invention uses a one-step synthesis method to efficiently construct a 3-methyl-3-quaternary carbon benzsulfonam core skeleton containing a quaternary carbon stereocenter and an optically active 2-aminoethylpyridine derivative, thereby expanding the molecular library of chiral benzsulfonam and 2-aminoethylpyridine candidate drugs.

[0088] The present invention further adopts peroxide as the alkyl free radical source to develop an economical and practical free radical type stereo convergent C (sp 3 The present invention can effectively capture highly active methyl radicals and control S H The stereochemistry of process 2 solves the synthetic difficulty of methylation / ethylation reaction.

[0089] The preparation method of the present invention avoids the use of harsh conditions such as strong acid, strong base, high temperature and the like and methyl metal reagents and noble metal salts, has mild reaction conditions and simple operation, and also has the advantages of high yield and high enantioselectivity.

[0090] The preparation method of the present invention has mild conditions, strong functional group tolerance, cheap reagents, high yield and high enantioselectivity, which not only effectively controls the synthesis cost, but also increases the feasibility of the method in the later derivatization and modification of candidate drugs.

[0091] In some of the examples, the photocatalytic reaction is followed by a step of separation using silica gel column chromatography; the eluent for the silica gel column chromatography includes a mixed solution of petroleum ether, acetone and dichloromethane or a mixed solution of petroleum ether and ethyl acetate.

[0092] Preferably, when the amine substrate to be alkylated is a benzsulfonam racemate, the eluent of the silica gel column chromatography comprises a mixed solution of petroleum ether, acetone and dichloromethane; the volume ratio of the petroleum ether, acetone and dichloromethane is (5-10):1:1.

[0093] Preferably, when the amine substrate to be alkylated is a 2-aminomethylpyridine derivative, the eluent of the silica gel column chromatography comprises a mixed solution of petroleum ether and ethyl acetate; the volume ratio of the petroleum ether to ethyl acetate is (3-15):1.

[0094] The embodiments of the present invention will be described in detail below in conjunction with examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods for which specific conditions are not specified in the following examples are preferably referred to the guidance given in the present invention, and can also be based on the experimental manual or conventional conditions in the art, or can also be based on the conditions recommended by the manufacturer, or refer to experimental methods known in the art. The reagents or instruments used that do not specify the manufacturer are all conventional products that can be obtained commercially.

[0095] In the following specific embodiments, the measured parameters of raw material components may have slight deviations within the range of weighing accuracy unless otherwise specified. For temperature and time parameters, acceptable deviations caused by instrument test accuracy or operation accuracy are allowed.

[0096] Example 1: Preparation of (R)-3-methyl-2,3-dihydrobenzo[d]isothiazole-3-carboxylic acid methyl ester-1,1-dioxide I-1:

[0097] In a glove box, ethylene glycol dimethyl ether nickel bromide (5 mol%, 3.1 mg), (3aS, 3a'S, 8aR, 8a'R)-2,2'-isopropylidenebis(3a,8a-dihydro-8H-indeno[1,2-d]oxazole) (6 mol%, 4.3 mg), [4,4'-di-tert-butyl-2,2'-bipyridine N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)]-1,4-diol ... )-2-pyridyl N]phenyl-C]iridium hexafluorophosphate (III) (1 mol%, 2.2 mg), then, 2,3-dihydrobenzo [d] isothiazole-3-carboxylic acid methyl ester 1,1-dioxide (0.20 mmol, 45.4 mg), hexafluoroisopropanol (0.32 mL), tert-butyl peroxide (2.0 eq., 0.072 mL) were added in sequence, 40W blue light was irradiated, and the reaction was reacted at room temperature for 48 hours. The reaction was monitored by TLC. After the reaction, the crude product was purified by silica gel column chromatography, eluted with petroleum ether / acetone / dichloromethane (6:1:1), and 40.5 mg of white solid was obtained, with a yield of 84%. A mixed solution of petroleum ether / acetone / dichloromethane = 2 / 1 / 1 was used as the developing solvent, R f =0.67, I-1 was prepared, and its chemical structure is as follows:

[0098]

[0099] 1 H NMR (400MHz, CDCl3) δ7.76-7.74(m, 1H), 7.70-7.64(m, 2H), 7.60-7.56(m, 1H), 5.77(s, 1H), 3.87(s, 3H), 1.87(s, 3H). 13 C NMR (101MHz, CDCl3) δ171.2, 139.2, 135.3, 133.7, 130.5, 124.9, 121.5, 65.5, 54.3, 27.6.HRMS (ESI): calculated for C 10 H 12 NO4S[M+H] + :242.0482,found:242.0483.HPLC:Daicel Chiralcel OD-H,n-hexane / isopropanol=90 / 10,flow rate 1.0mL / min.λ=210 nm,t R (minor) = 19.966min, t R(major)=22.785min,98:2er.[α] 25 D = +7.4° (c = 1.00 in CHCl3).

[0100] Example 2: Preparation of (R)-5-fluoro-3-methyl-2,3-dihydrobenzo[d]isothiazole-3-carboxylic acid methyl ester 1,1-dioxide I-2:

[0101] In a glove box, ethylene glycol dimethyl ether nickel bromide (5 mol%, 3.1 mg), (3aS, 3a'S, 8aR, 8a'R)-2,2'-isopropylidenebis(3a,8a-dihydro-8H-indeno[1,2-d]oxazole) (6 mol%, 4.3 mg), [4,4'-di-tert-butyl-2,2'-bipyridine N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)- 2-pyridyl N] phenyl-C] iridium hexafluorophosphate (III) (1 mol%, 2.2 mg), then, 5-fluoro-2,3-dihydrobenzo [d] isothiazole-3-carboxylic acid methyl ester 1,1-dioxide (0.20 mmol, 49.0 mg), hexafluoroisopropanol (0.32 mL), tert-butyl peroxide (2.0 eq., 0.072 mL) were added in sequence, 40W blue light was irradiated, and the reaction was reacted at room temperature for 48 hours. The reaction was monitored by TLC. After the reaction, the crude product was purified by silica gel column chromatography, eluted with petroleum ether / acetone / dichloromethane (6:1:1), and 46.2 mg of white solid was obtained, with a yield of 89%. A mixed solution of petroleum ether / acetone / dichloromethane = 2 / 1 / 1 was used as the developing solvent, R f =0.53, I-2 was prepared, and its chemical structure is as follows:

[0102]

[0103] 1 H NMR (400MHz, CDCl3) δ7.77-7.73 (m, 1H), 7.38-7.35 (m, 1H), 7.30-7.25 (m, 1H), 5.86 (s, 1H), 3.90 (s, 3H), 1.86 (s, 3H). 13 C NMR (101MHz, CDCl3) δ170.6, 165.8 (d, J=256.6Hz), 142.4 (d, J=9.2Hz), 131.4 (d, J=2.9 Hz), 123.8 (d, J=10.0Hz), 118.5 (d, J=24.3Hz), 112.3 (d, J=25.0Hz), 65.0, 54.5, 27.6. 19F NMR(377MHz, CDCl3)δ-103.3(m).HRMS(ESI): calculated for C 10 H 11 FNO4S[M+H] + : 260.0387, found: 260.0389.HPLC: DaicelChiralcel OD-H, n-hexane / isopropanol = 90 / 10, flow rate 1.0 mL / min, λ = 210 nm, t R (minor) = 17.253min, t R (major)=21.069min, 98.5: 1.5er.[α] 25 D = +8.8° (c = 0.73 in CHCl3).

[0104] Example 3: Preparation of (R)-5-chloro-3-methyl-2,3-dihydrobenzo[d]isothiazole-3-carboxylic acid methyl ester 1,1-dioxide I-3:

[0105] In a glove box, ethylene glycol dimethyl ether nickel bromide (5 mol%, 3.1 mg), (3aS, 3a'S, 8aR, 8a'R)-2,2'-isopropylidenebis(3a,8a-dihydro-8H-indeno[1,2-d]oxazole) (6 mol%, 4.3 mg), [4,4'-di-tert-butyl-2,2'-bipyridine N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)- 2-pyridyl N] phenyl-C] iridium hexafluorophosphate (III) (1 mol%, 2.2 mg), then, 5-chloro-2,3-dihydrobenzo [d] isothiazole-3-carboxylic acid methyl ester 1,1-dioxide (0.20 mmol, 55.0 mg), hexafluoroisopropanol (0.32 mL), tert-butyl peroxide (2.0 eq., 0.072 mL) were added in sequence, 40W blue light was irradiated, and the reaction was reacted at room temperature for 48 hours. The reaction was monitored by TLC. After the reaction, the crude product was purified by silica gel column chromatography, eluted with petroleum ether / acetone / dichloromethane (6:1:1), and 52.5 mg of white solid was obtained, with a yield of 95%. A mixed solution of petroleum ether / acetone / dichloromethane = (2:1:1) was used as the developing solvent, R f =0.60, I-3 was prepared, and its chemical structure is as follows:

[0106]

[0107] 1H NMR (400MHz, CDCl3) δ7.70-7.66 (m, 2H), 7.56-7.53 (m, 1H), 5.86 (s, 1H), 3.90 (s, 3H), 1.86 (s, 3H). 13 C NMR (101MHz, CDCl3) δ170.6, 141.2, 140.2, 133.9, 131.0, 125.2, 122.7, 65.1, 54.5, 27.5.HRMS (ESI): calculated for C 10 H 10 ClNO4S[M+H] + : 276.0092, found: 276.0093. HPLC: Daicel Chiralcel OD-H, n-hexane / isopropanol = 90 / 10, flow rate 1.0 mL / min, λ = 210 nm, t R (minor) = 16.315min, t R (major)=18.912min,96:4er.[α] 25 D =-18.8°(c=0.70in CHCl3).

[0108] Example 4: Preparation of (R)-7-chloro-3-methyl-2,3-dihydrobenzo[d]isothiazole-3-carboxylic acid methyl ester 1,1-dioxide I-4:

[0109] In a glove box, ethylene glycol dimethyl ether nickel bromide (5 mol%, 3.1 mg), (3aS, 3a'S, 8aR, 8a'R)-2,2'-isopropylidenebis(3a,8a-dihydro-8H-indeno[1,2-d]oxazole) (6 mol%, 4.3 mg), [4,4'-di-tert-butyl-2,2'-bipyridine N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)- 2-pyridyl N] phenyl-C] iridium hexafluorophosphate (III) (1 mol%, 2.2 mg), then, 7-chloro-2,3-dihydrobenzo [d] isothiazole-3-carboxylic acid methyl ester 1,1-dioxide (0.20 mmol, 55.0 mg), hexafluoroisopropanol (0.32 mL), tert-butyl peroxide (2.0 eq., 0.072 mL) were added in sequence, 40W blue light was irradiated, and the reaction was reacted at room temperature for 48 hours. The reaction was monitored by TLC. After the reaction, the crude product was purified by silica gel column chromatography, eluted with petroleum ether / acetone / dichloromethane (6:1:1), and 49.5 mg of white solid was obtained, with a yield of 90%. A mixed solution of petroleum ether / acetone / dichloromethane = (2:1:1) was used as the developing solvent, R f=0.60, I-4 was prepared, and its chemical structure is as follows:

[0110]

[0111] 1 H NMR (400MHz, CDCl3) δ7.60-7.56 (m, 2H), 7.53-7.49 (m, 1H), 5.85 (s, 1H), 3.89 (s, 3H), 1.86 (s, 3H). 13 C NMR (101MHz, CDCl3) δ170.7, 142.0, 134.8, 133.5, 131.3, 129.2, 123.1, 64.6, 54.4, 27.5.HRMS (ESI): calculated for C 10 H 11 ClNO4S[M+H] + : 276.0092, found: 276.0093. HPLC: Daicel Chiralpak IA, n-hexane / isopropanol = 90 / 10, flow rate 1.0 mL / min, λ = 210 nm, t R (major) = 20.382min, t R (minor)=23.429min, 97.5: 2.5er.[α] 25 D = +35.8° (c = 0.45 in CHCl3).

[0112] Example 5: Preparation of (R)-5-phenyl-3-methyl-2,3-dihydrobenzo[d]isothiazole-3-carboxylic acid methyl ester 1,1-dioxide I-5:

[0113] In a glove box, ethylene glycol dimethyl ether nickel bromide (5 mol%, 3.1 mg), (3aS, 3a'S, 8aR, 8a'R)-2,2'-isopropylidenebis(3a,8a-dihydro-8H-indeno[1,2-d]oxazole) (6 mol%, 4.3 mg), [4,4'-di-tert-butyl-2,2'-bipyridine N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)- 2-pyridyl N] phenyl-C] iridium hexafluorophosphate (III) (1 mol%, 2.2 mg), then, 5-phenyl-2,3-dihydrobenzo [d] isothiazole-3-carboxylic acid methyl ester l, 1-dioxide (0.20 mmol, 63.4 mg), hexafluoroisopropanol (0.32 mL), tert-butyl peroxide (2.0 eq., 0.072 mL) were added in sequence, 40W blue light was irradiated, and the reaction was reacted at room temperature for 48 hours, and the reaction was monitored by TLC. After the reaction, the crude product was purified by silica gel column chromatography, eluted with petroleum ether / acetone / dichloromethane (6:1:1), and 61.0 mg of white solid was obtained, with a yield of 96%. A mixed solution of petroleum ether / acetone / dichloromethane = (2:1:1) was used as the developing solvent, R f =0.46, I-5 was prepared, and its chemical structure is as follows:

[0114]

[0115] 1 H NMR (400MHz, CDCl3) δ7.84-7.70 (m, 3H), 7.60-7.58 (m, 2H), 7.53-7.44 (m, 3H), 5.83 (s, 1H), 3.90 (s, 3H), 1.93 (s, 3H). 13 C NMR (101MHz, CDCl3) δ171.2, 147.4, 140.1, 139.3, 133.9, 129.7, 129.3, 129.0, 127.7, 123.3, 121.9, 65.6, 54.4, 27.8.HRMS (ESI): calculated for C 16 H 16 NO4S[M+H] + : 318.0795, found: 318.0796. HPLC: Daicel Chiralcel OD-H, n-hexane / isopropanol = 90 / 10, flow rate 1.0 mL / min, λ = 210 nm, t R (minor) = 23.502min, t R (major)=28.090min,98:2er.[α] 25D =-43.0°(c=1.00in CHCl3)

[0116] Example 6: Preparation of (R)-5-trifluoromethoxy-3-methyl-2,3-dihydrobenzo[d]isothiazole-3-carboxylic acid methyl ester 1,1-dioxide I-6:

[0117] In a glove box, ethylene glycol dimethyl ether nickel bromide (5 mol%, 3.1 mg), (3aS, 3a'S, 8aR, 8a'R)-2,2'-isopropylidenebis(3a,8a-dihydro-8H-indeno[1,2-d]oxazole) (6 mol%, 4.3 mg), [4,4'-di-tert-butyl-2,2'-bipyridine N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2- Pyridyl N]phenyl-C]iridium hexafluorophosphate (III) (1 mol%, 2.2 mg), then, 5-trifluoromethoxy-2,3-dihydrobenzo[d]isothiazole-3-carboxylic acid methyl ester 1,1-dioxide (0.20 mmol, 62.2 mg), hexafluoroisopropanol (0.32 mL), tert-butyl peroxide (2.0 eq., 0.072 mL) were added in sequence, 40W blue light was irradiated, and the reaction was reacted at room temperature for 48 hours. The reaction was monitored by TLC. After the reaction, the crude product was purified by silica gel column chromatography, eluted with petroleum ether / acetone / dichloromethane (6:1:1), and 57.7 mg of white solid was obtained, with a yield of 89%. A mixed solution of petroleum ether / acetone / dichloromethane = (2:1:1) was used as the developing solvent, R f =0.53, I-6 was prepared, and its chemical structure is as follows:

[0118]

[0119] 1 H NMR (400MHz, CDCl3) δ7.80 (d, J=8.4Hz, 1H), 7.51 (s, 1H), 7.44-7.42 (m, 1H), 5.87 (s, 1H), 3.91 (s, 3H), 1.88 (s, 3H). 13 C NMR (101MHz, CDCl3) δ170.5, 153.0 (q, J=1.7Hz), 141.9, 133.7, 123.4, 123.0, 120.3 (q, J=261.1Hz), 117.3, 65.1, 54.5, 27.6. 19 FNMR(377MHz, CDCl3)δ-57.8.HRMS(ESI): calculated for C 11 H 11 F3NO5S[M+H]+ : 326.0305, found: 326.0306.HPLC: Daicel Chiralcel OD-H, n-hexane / isopropanol 90 / 10, flow rate 1.0 mL / min, λ=210 nm, t R (minor) = 12.658min, t R (major)=15.546min, 93.5: 6.5er.[α] 25 D =-1.2°(c=0.74in CHCl3).

[0120] Example 7: Preparation of (R)-5-tert-butyl-3-methyl-2,3-dihydrobenzo[d]isothiazole-3-carboxylic acid methyl ester 1,1-dioxide I-7:

[0121] In a glove box, ethylene glycol dimethyl ether nickel bromide (5 mol%, 3.1 mg), (3aS, 3a'S, 8aR, 8a'R)-2,2'-isopropylidenebis(3a,8a-dihydro-8H-indeno[1,2-d]oxazole) (6 mol%, 4.3 mg), [4,4'-di-tert-butyl-2,2'-bipyridine N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2 -pyridyl N]phenyl-C]iridium hexafluorophosphate (III) (1 mol%, 2.2 mg), then, 5-tert-butyl-2,3-dihydrobenzo[d]isothiazole-3-carboxylic acid methyl ester 1,1-dioxide (0.20 mmol, 56.6 mg), hexafluoroisopropanol (0.32 mL), tert-butyl peroxide (2.0 eq., 0.072 mL) were added in sequence, 40W blue light was irradiated, and the reaction was reacted at room temperature for 43 hours, and the reaction was monitored by TLC. After the reaction, the crude product was purified by silica gel column chromatography, eluted with petroleum ether / acetone / dichloromethane (6:1:1), and 55.8 mg of white solid was obtained, with a yield of 94%. A mixed solution of petroleum ether / acetone / dichloromethane = (2:1:1) was used as the developing solvent, R f =0.57, I-7 was prepared, and its chemical structure is as follows:

[0122]

[0123] 1 H NMR (400MHz, CDCl3) δ7.68-7.60 (m, 3H), 5.73 (s, 1H), 3.88 (s, 3H), 1.87 (s, 3H), 1.36 (s, 9H). 13C NMR (101MHz, CDCl3) δ171.3, 158.2, 139.4, 132.5, 128.1, 121.3, 121.0, 65.6, 54.1, 35.7, 31.3, 27.7.HRMS (ESI): calculated for C 14 H 20 NO4S[M+H]+: 298.1108, found: 298.1110. HPLC: Daicel Chiralcel OD-H, n-hexane / isopropanol = 90 / 10, flow rate 1.0 mL / min, λ = 210 nm, t R (minor) = 24.607min, t R (major)=30.665min, 83:17er.[α] 25 D =-2.8°(c=0.80in CHCl3).

[0124] Example 8: Preparation of (R)-5-methoxy-3-methyl-2,3-dihydrobenzo[d]isothiazole-3-carboxylic acid methyl ester 1,1-dioxide I-8:

[0125] In a glove box, ethylene glycol dimethyl ether nickel bromide (5 mol%, 3.1 mg), (3aS, 3a'S, 8aR, 8a'R)-2,2'-isopropylidenebis(3a,8a-dihydro-8H-indeno[1,2-d]oxazole) (6 mol%, 4.3 mg), [4,4'-di-tert-butyl-2,2'-bipyridine N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2 -pyridyl N]phenyl-C]iridium hexafluorophosphate (III) (1 mol%, 2.2 mg), then, 5-methoxy-2,3-dihydrobenzo [d] isothiazole-3-carboxylic acid methyl ester 1,1-dioxide (0.20 mmol, 51.4 mg), hexafluoroisopropanol (0.32 mL), tert-butyl peroxide (2.0 eq., 0.072 mL) were added in sequence, 40W blue light was irradiated, and the reaction was reacted at room temperature for 48 hours. The reaction was monitored by TLC. After the reaction, the crude product was purified by silica gel column chromatography, eluted with petroleum ether / acetone / dichloromethane (6:1:1), and 50.1 mg of white solid was obtained, with a yield of 92%. A mixed solution of petroleum ether / acetone / dichloromethane = (2:1:1) was used as the developing solvent, R f =0.60, I-8 was prepared, and its chemical structure is as follows:

[0126]

[0127] 1H NMR (400MHz, CDCl3) δ7.65 (d, J=8.4Hz, 1H), 7.09-7.05 (m, 2H), 5.73 (s, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 1.85 (s, 3H). 13 C NMR (101MHz, CDCl3) δ171.1, 164.1, 141.9, 127.4, 122.9, 116.8, 109.4, 65.2, 56.1, 54.2, 27.7.HRMS (ESI): calculated for C 11 H 14 NO5S[M+H] + : 272.0587, found: 272.0590.HPLC: Daicel Chiralcel OD-H, n-hexane / isopropanol = 90 / 10, flow rate 1.0 mL / min, λ = 210 nm, t R (minor) = 26.458min, t R (major)=30.139min,98:2er.[α] 25 D =-13.8°(c=0.39inCHCl3).

[0128] Example 9: Preparation of (R)-3-methyl-2,3-dihydronaphtho[2,1-d]isothiazole-3-carboxylic acid methyl ester 1,1-dioxide I-9: In a glove box, ethylene glycol dimethyl ether nickel bromide (5 mol%, 3.1 mg), (3aS, 3a'S, 8aR, 8a'R)-2,2′-isopropylidenebis(3a,8a-dihydro-8H-indeno[1,2-d]oxazole) (6 mol%, 4.3 mg), [4,4′-di-tert-butyl-2,2′-bipyridine N 1, N1′] bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl N]phenyl-C] iridium hexafluorophosphate (III) (1 mol%, 2.2 mg), then, 2,3-dihydronaphtho[2,1-d]isothiazole-3-carboxylic acid methyl ester 1,1-dioxide (0.20 mmol, 55.4 mg), hexafluoroisopropanol (0.32 mL), tert-butyl peroxide (2.0 eq., 0.072 mL) were added in sequence, 40 W blue light was irradiated, and the reaction was reacted at room temperature for 58 hours, and the reaction was monitored by TLC. After the reaction, the crude product was purified by silica gel column chromatography, eluted with petroleum ether / acetone / dichloromethane (6:1:1), and 56.3 mg of white solid was obtained, with a yield of 97%. A mixed solution of petroleum ether / acetone / dichloromethane = (2:1:1) was used as the developing solvent, R f=0.50, I-9 was prepared, and its chemical structure is as follows:

[0129]

[0130] 1 H NMR (400MHz, CDCl3) δ8.40 (d, J=8.0Hz, 1H), 8.10 (d, J=8.8Hz, 1H), 7.97 (d, J=8.0Hz, 1H), 7.75-7.64 (m, 3H), 5.93 (s, 1H), 3.89 (s, 3H), 1.94 (s, 3H). 13 C NMR (101MHz, CDCl3) δ171.2, 138.2, 134.9, 134.0, 130.7, 129.5, 128.7, 128.4, 125.4, 123.4, 120.5, 65.5, 54.3, 27.3.HRMS (ESI): calculated for C 14 H 14 NO4S[M+H] + : 292.0638, found: 292.0641. HPLC: Daicel Chiralcel OD-H, n-hexane / isopropanol = 90 / 10, flow rate 1.0 mL / min, λ = 210 nm, t R (minor) = 21.681min, t R (major)=23.223min,98:2er.[α] 25 D = +50.6° (c = 0.57 in CHCl3).

[0131] Example 10: Preparation of (R)-4-methyl-3,4-dihydrobenzo[e][1,2,3]thiazine-4-carboxylic acid methyl ester 2,2-dioxide I-10:

[0132] In a glove box, ethylene glycol dimethyl ether nickel bromide (5 mol%, 3.1 mg), (3aS, 3a'S, 8aR, 8a'R)-2,2'-isopropylidenebis(3a,8a-dihydro-8H-indeno[1,2-d]oxazole) (6 mol%, 4.3 mg), [4,4'-di-tert-butyl-2,2'-bipyridine N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2 -pyridyl N]phenyl-C]iridium hexafluorophosphate (III) (1 mol%, 2.2 mg), then, 3,4-dihydrobenzo [e] [1,2,3] thiazine-4-carboxylic acid methyl ester 2,2-dioxide (0.20 mmol, 48.6 mg), hexafluoroisopropanol (0.32 mL), tert-butyl peroxide (2.0 eq., 0.072 mL) were added in sequence, 40W blue light was irradiated, and the reaction was reacted at room temperature for 48 hours, and the reaction was monitored by TLC. After the reaction, the crude product was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (10:1), and 46.7 mg of white solid was obtained, with a yield of 91%. A mixed solution of petroleum ether / ethyl acetate = (2:1) was used as a developing solvent, R f =0.65, I-10 was prepared, and its chemical structure is as follows:

[0133]

[0134] 1 H NMR (400MHz, CDCl3) δ7.56 (dd, J=8.0, 2.0Hz, 1H), 7.38-7.33 (m, 1H), 7.25-7. 20 (m, 1H), 7.03 (dd, J=8.4, 1.6Hz, 1H), 6.14 (s, 1H), 3.89 (s, 3H), 2.00 (s, 3H). 13 C NMR (101MHz, CDCl3) δ171.2, 150.2, 130.7, 127.8, 125.9, 121.4, 119.7, 65.5, 54.5, 26.9.HRMS (ESI): calculated for C 10 H 12 NO5S[M+H] + : 258.0431, found: 258.0431. HPLC: Daicel Chiralpak ID, n-hexane / isopropanol = 90 / 10, flow rate 1.0 mL / min, λ = 210 nm, t R (minor) = 16.149min, t R (major)=18.653min, 92:8er.[α] 25D = +1.1° (c = 1.00 in CHCl3).

[0135] Example 11: Preparation of (R)-3-methyl-2,3-dihydrobenzo[d]isothiazole-3-carboxylic acid butyl ester-1,1-dioxide I-11: In a glove box, ethylene glycol dimethyl ether nickel bromide (5 mol%, 3.1 mg), (3aS, 3a'S, 8aR, 8a'R)-2,2′-isopropylidenebis(3a,8a-dihydro-8H-indeno[1,2-d]oxazole) (6 mol%, 4.3 mg), [4,4′-di-tert-butyl-2,2′-bipyrrolidone] pyridinium N1, N1′] bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl N]phenyl-C] iridium hexafluorophosphate (III) (1 mol%, 2.2 mg), then, 2,3-dihydrobenzo[d]isothiazole-3-carboxylic acid butyl ester 1,1-dioxide (0.20 mmol, 53.8 mg), hexafluoroisopropanol (0.32 mL), tert-butyl peroxide (2.0 eq., 0.072 mL) were added in sequence, 40 W blue light was irradiated, and the reaction was reacted at room temperature for 48 hours, and the reaction was monitored by TLC. After the reaction, the crude product was purified by silica gel column chromatography, eluted with petroleum ether / acetone / dichloromethane (6:1:1), and 48.8 mg of white solid was obtained, with a yield of 86%. A mixed solution of petroleum ether / acetone / dichloromethane (6:1:1) was used as the developing solvent, R f =0.55, I-11 was prepared, and its chemical structure is as follows:

[0136]

[0137] 1 H NMR (400MHz, CDCl3) δ7.76 (d, J=7.6Hz, 1H), 7.70-7.65 (m, 2H), 7.60-7.56 (m, 1H), 5.78 (s, 1H) , 4.32-4.21 (m, 2H), 1.86 (s, 3H), 1.73-1.66 (m, 2H), 1.44-1.36 (m, 2H), 0.94 (t, J=7.6Hz, 3H). 13 C NMR (101MHz, CDCl3) δ170.7, 139.5, 135.4, 133.6, 130.5, 124.8, 121.5, 67.5, 65.6, 30.6, 27.6, 19.1, 13.7.HRMS (ESI): calculated for C 13 H 17 NNaO4S[M+Na] +:306.0770, found:306.0771.HPLC:Daicel Chiralcel AD-H, n-hexane / isopropanol=85 / 15, flow rate 1.0mL / min, λ=210nm, t R (minor) = 11.734min, t R (major)=15.363min,99.5:0.5er.[α] 25 D = +18.3° (c = 1.00 in CHCl3).

[0138] Example 12: Preparation of (R)-3-methyl-2,3-dihydrobenzo[d]isothiazole-3-carboxylic acid (2-methoxy)ethyl ester-1,1-dioxide I-12:

[0139] In a glove box, ethylene glycol dimethyl ether nickel bromide (5 mol%, 3.1 mg), (3aS, 3a'S, 8aR, 8a'R)-2,2'-isopropylidenebis(3a,8a-dihydro-8H-indeno[1,2-d]oxazole) (6 mol%, 4.3 mg), [4,4'-di-tert-butyl-2,2'-bipyridine N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)- 2-pyridyl N]phenyl-C]iridium hexafluorophosphate (III) (1 mol%, 2.2 mg), then, 2,3-dihydrobenzo [d] isothiazole-3-carboxylic acid 2-methoxyethyl ester 1,1-dioxide (0.20 mmol, 54.3 mg), hexafluoroisopropanol (0.32 mL), tert-butyl peroxide (3.0 eq., 0.108 mL) were added in sequence, 40W blue light was irradiated, and the reaction was reacted at room temperature for 24 hours. The reaction was monitored by TLC. After the reaction, the crude product was purified by silica gel column chromatography, eluted with petroleum ether / acetone / dichloromethane (8:1:1), and 43.4 mg of colorless oily liquid was obtained, with a yield of 76%. A mixed solution of petroleum ether / acetone / dichloromethane (4:1:1) was used as the developing solvent, R f =0.50, I-12 was prepared, and its chemical structure is as follows:

[0140]

[0141] 1 H NMR (400MHz, CDCl3) δ7.75 (t, J=7.2Hz, 2H), 7.65-7.63 (m, 1H), 7.60-7.56 (m, 1H ), 5.86 (s, 1H), 4.46-4.35 (m, 2H), 3.68-3.57 (m, 2H), 3.36 (s, 3H), 1.88 (s, 3H).13 C NMR (101MHz, CDCl3) δ170.7, 139.4, 135.4, 133.6, 130.5, 125.0, 121.4, 70.0, 66.1, 65.6, 59.0, 27.5.HRMS (ESI): calculated for C 12 H 16 NO5S[M+H] + : 286.0744, found: 286.0743. HPLC: Daicel Chiralcel OD-H, n-hexane / isopropanol = 90 / 10, flow rate 1.0 mL / min, λ = 254 nm, t R (minor) = 21.076min, t R (major)=25.077min,94.5:5.5er.[α] 25 D =+20.8°(c=0.83in CHCl3)..

[0142] Example 13: Preparation of (R)-3-methyl-2,3-dihydrobenzo[d]isothiazole-3-carboxylic acid 2-(4-iodophenylamide)ethyl ester-1,1-dioxide I-13:

[0143] In a glove box, ethylene glycol dimethyl ether nickel bromide (10 mol%, 6.2 mg), (3aS, 3a'S, 8aR, 8a'R)-2,2'-isopropylidenebis(3a,8a-dihydro-8H-indeno[1,2-d]oxazole) (12 mol%, 8.6 mg), [4,4'-di-tert-butyl-2,2'-bipyridine N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2- Pyridyl N]phenyl-C]iridium hexafluorophosphate (III) (1 mol%, 2.2 mg), then, 2,3-dihydrobenzo[d]isothiazole-3-carboxylic acid 2-(4-iodophenylamide)ethyl ester-1,1-dioxide (0.20 mmol, 97.3 mg), hexafluoroisopropanol (0.32 mL), tert-butyl peroxide (5.0 eq., 0.18 mL) were added in sequence, 40W blue light was irradiated, and the reaction was reacted at room temperature for 24 hours, and the reaction was monitored by TLC. After the reaction, the crude product was purified by silica gel column chromatography, eluted with petroleum ether / acetone / dichloromethane (6:1:1), and 87.9 mg of colorless oily liquid was obtained, with a yield of 88%. A mixed solution of petroleum ether / acetone / dichloromethane (2:1:1) was used as the developing solvent, R f =0.37, I-13 was prepared, and its chemical structure is as follows:

[0144]

[0145] 1 H NMR (400MHz, CDCl3) δ7.75-7.70(m, 3H), 7.62-7.52(m, 3H), 7.45-7.43(m, 2H), 6. 94-6.91 (m, 1H), 5.61 (s, 1H), 4.32 (t, J = 4.8Hz, 2H), 3.69 (q, J = 5.6Hz, 2H), 1.88 (s , 3H).13CNMR (101MHz, CDCl3) δ170.6, 167.0, 138.8, 137.8, 134.7, 134.0, 133.3, 130.6, 128.9, 124.7, 121.3, 98.8, 65.9, 65.3, 38.8, 25.8.HRMS (ESI): calculated forC 18 H 18 IN2O5S[M+H] + :500.9976.found:500.9972.

[0146] HPLC: Daicel Chiralcel OD-H, n-hexane / isopropanol = 90 / 10, flow rate 1.0 mL / min, λ = 210 nm, t R (minor) = 71.307min, t R (major)=83.197min,97.5:2.5er.[α] 25 D =-51.1°(c=0.65in CHCl3).

[0147] Example 14: Preparation of (R)-3-methyl-2,3-dihydrobenzo[d]isothiazole-3-carboxylic acid 2-(thiophen-2-yl)ethyl ester-1,1-dioxide I-14:

[0148] In a glove box, ethylene glycol dimethyl ether nickel bromide (5 mol%, 3.1 mg), (3aS, 3a'S, 8aR, 8a'R)-2,2'-isopropylidenebis(3a,8a-dihydro-8H-indeno[1,2-d]oxazole) (6 mol%, 4.3 mg), [4,4'-di-tert-butyl-2,2'-bipyridine N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridine]-1,2-d]oxazole (6 mol%, 4.3 mg), and 1,5-difluoro-2-[5-(trifluoromethyl)-2-pyridine]-1,2-d]oxazole (6 mol%, 4.3 mg) were added to a dry 1.5 mL clear glass vial. Pyridyl N]phenyl-C]iridium hexafluorophosphate (III) (1 mol%, 2.2 mg), then, 2,3-dihydrobenzo[d]isothiazole-3-carboxylic acid 2-(thiophen-2-yl)ethyl ester-1,1-dioxide (0.20 mmol, 64.7 mg), hexafluoroisopropanol (0.32 mL), tert-butyl peroxide (5.0 eq., 0.18 mL) were added in sequence, 40 W blue light was irradiated, and the reaction was reacted at room temperature for 24 hours, and the reaction was monitored by TLC. After the reaction, the crude product was purified by silica gel column chromatography, eluted with petroleum ether / acetone / dichloromethane (6:1:1), and 18.0 mg of colorless oily liquid was obtained, with a yield of 27%. A mixed solution of petroleum ether / acetone / dichloromethane (4:1:1) was used as the developing solvent, R f =0.47, I-14 was prepared, and its chemical structure is as follows:

[0149]

[0150] 1 H NMR (400MHz, CDCl3) δ7.86-7.73 (m, 1H), 7.56-7.55 (m, 2H), 7.48-7.45 (m, 1H), 7.20-7.19 (m, 1H), 6.9 6-6.94 (m, 1H), 6.85-6.84 (m, 1H), 5.72 (s, 1H), 4.54-4.43 (m, 2H), 3.25 (t, J=6.4Hz, 2H), 1.83 (s, 3H). 13 C NMR (101MHz, CDCl3) δ170.6, 139.2, 139.1, 135.3, 133.7, 130.4, 127.2, 126.1, 124.9, 124.5, 121.5, 67.5, 65.5, 29.2, 27.5.HRMS (ESI): calculated for C 15 H 15 KNO4S2[M+K] + : 376.0074, found: 376.0075. HPLC: Daicel Chiralcel OD-H, n-hexane / isopropanol = 90 / 10, flow rate 1.0 mL / min, λ = 210 nm, tR (minor) = 35.321min, t R (major)=43.743min, 92.5: 7.5er.[α] 25 D = +23.9° (c = 0.81 in CHCl3).

[0151] Example 15: Preparation of (S)-3-methyl-2,3-dihydrobenzo[d]isothiazole-3-carboxylic acid 2-(phenoxy)acetamide-1,1-dioxide I-15:

[0152] In a glove box, ethylene glycol dimethyl ether nickel bromide (10 mol%, 6.2 mg), (4S, 4′S)-2,2′-cyclopentylidenebis[4,5-dihydro-4-phenyloxazole] (12 mol%, 8.7 mg), [4,4′-di-tert-butyl-2,2′-bipyridine N1,N1′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl N]phenyl- C] iridium (III) hexafluorophosphate (1 mol%, 2.2 mg), then, 2,3-dihydrobenzo[d]isothiazole-3-carboxylic acid 2-(phenoxy)acetamide 1,1-dioxide (0.20 mmol, 66.5 mg), hexafluoroisopropanol (0.32 mL), tert-butyl peroxide (5.0 eq., 0.18 mL) were added in sequence, 40 W blue light was irradiated, and the reaction was reacted at room temperature for 24 hours, and the reaction was monitored by TLC. After the reaction, the crude product was purified by silica gel column chromatography, eluted with petroleum ether / acetone / dichloromethane (6:1:1), and 27.0 mg of colorless oily liquid was obtained, with a yield of 39%. A mixed solution of petroleum ether / acetone / dichloromethane (4:1:1) was used as the developing solvent, R f =0.45, I-15 was prepared, and its chemical structure is as follows:

[0153]

[0154] 1 H NMR (400MHz, CDCl3) δ7.85 (d, J=8.0Hz, 1H), 7.71 (d, J=7.6Hz, 1H), 7.65 (t, J=7.6Hz, 1H), 7.57-7.54 (m, 2H), 7.28-7.24 (m, 2H), 6.96 (t, J=7.6Hz, 1H), 6.87 (d, J=8.4Hz, 2H), 5.15 (s, 1H), 4.06-3.95 (m, 2H), 3.73-3.66 (m, 1H), 3.54-3.46 (m, 1H), 1.88 (s, 3H). 13C NMR (101MHz, CDCl3) δ170.7, 158.6, 140.3, 134.0, 133.9, 130.3, 129.6, 125.6, 121.4, 121.0, 114.9, 66.3, 65.8, 39.7, 26.3.HRMS (ESI): calculated for C 17 H 19 N2O4S[M+H] + : 347.1060, found: 347.1061. HPLC: Daicel Chiralpak IB, n-hexane / isopropanol=80 / 20, flow rate 1.0 mL / min, λ=210 nm, t R (minor) = 11.369min, t R (major)=22.838min, 96.5:3.5er.[α] 25 D = +45.5° (c = 0.67 in CHCl3).

[0155] Example 16: Preparation of (R)-3-methyl-2,3-dihydrobenzo[d]isothiazole-3-carboxylic acid ((3aR, 5R, 5aS, 8aS, 8bR)-2,2,7,7-tetramethyltetrahydro-5H-bis([1,3]dioxy)[4,5-b:4′,5′-d]pyran-5-yl)methyl ester-1,1-dioxide I-16:

[0156] In a glove box, ethylene glycol dimethyl ether nickel bromide (10 mol%, 6.2 mg), (3aS, 3a'S, 8aR, 8a'R)-2,2'-isopropylidenebis(3a,8a-dihydro-8H-indeno[1,2-d]oxazole) (12 mol%, 8.6 mg), [4,4'-di-tert-butyl-2,2'-bipyridine N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl N]phenyl-C]iridium(III)hexafluorophosphate (1 mol%, 2.2 mg) were added to a dry 1.5 mL clear glass vial. g), then, 2,3-dihydrobenzo[d]isothiazole-3-carboxylic acid ((3aR, 5R, 5aS, 8aS, 8bR)-2,2,7,7-tetramethyltetrahydro-5H-bis([1,3]dioxy)[4,5-b:4′,5′-d]pyran-5-yl)methyl ester-1,1-dioxide (0.20 mmol, 91.1 mg), hexafluoroisopropanol (0.32 mL), tert-butyl peroxide (2.0 eq., 0.072 mL) were added in sequence, 40 W blue light was irradiated, the reaction was reacted at room temperature for 24 hours, and the reaction was monitored by TLC. After the reaction, the crude product was purified by silica gel column chromatography, eluted with petroleum ether / acetone / dichloromethane (6:1:1), and 63.1 mg of colorless oily liquid was obtained with a yield of 67%. A mixed solution of petroleum ether / acetone / dichloromethane (3:1:1) was used as the developing solvent. f =0.51, I-16 was prepared, and its chemical structure is as follows:

[0157]

[0158] 1 H NMR (600MHz, CDCl3) δ7.79 (d, J=7.8Hz, 1H), 7.74 (d, J=7.8Hz, 1H), 7.64 (t, J=7.5Hz, 1H), 7.56 (t, J=7.5Hz, 1H), 5.81 (s, 1H), 5.54 (d, J=4.8Hz, 1H), 4.61 (dd, J=8.4, 3.0H z, 1H), 4.53 (dd, J=11.4, 3.0Hz, 1H), 4.37-4.32 (m, 2H), 4.21 (dd, J=7.8, 1.8Hz, 1H), 3.96-3.93 (m, 1H), 1.88 (s, 3H), 1.47 (s, 3H), 1.33 (s, 3H), 1.30 (s, 3H), 1.27 (s, 3H). 13CNMR (101MHz, CDCl3) δ170.8, 139.3, 135.3, 133.9, 130.3, 125.6, 121.3, 110.1, 108.9, 96.4, 71.1, 70.9, 70.5, 66.3, 66.1, 65.6, 27.6, 26.1, 26.0, 25.1, 24.5.HRMS(ESI): calculatedfor C 21 H 28 NO9S[M+H] + : 470.1479, found: 470.1480.HPLC: Daicel Chiralcel OD-H, n-hexane / isopropanol = 90 / 10, flow rate 1.0 mL / min, λ = 210 nm, t R (minor) = 16.983min, t R (major)=20.266min, 91.5: 8.5dr.[α] 25 D =-29.8°(c=1.00in CHCl3).

[0159] Example 17: Preparation of (S)-4-(3-methyl-1,1-dioxo-2,3-dihydrophenylpropano[d]isothiazole-3-carboxamido)butyric acid methyl ester I-17:

[0160] In a glove box, ethylene glycol dimethyl ether nickel bromide (10 mol%, 6.2 mg), (4S, 4'S)-2,2'-cyclopentylidenebis[4,5-dihydro-4-phenyloxazole] (12 mol%, 8.7 mg), [4,4'-di-tert-butyl-2,2'-bipyridyl N1, N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl N]phenyl- C] iridium (III) hexafluorophosphate (1 mol%, 2.2 mg), then, 4-(1,1-dioxo-2,3-dihydrophenylpropano[d]isothiazole-3-carboxamido)butyric acid methyl ester (0.20 mmol, 62.5 mg), hexafluoroisopropanol (0.32 mL), tert-butyl peroxide (5.0 eq., 0.18 mL) were added in sequence, 40 W blue light was irradiated, and the reaction was reacted at room temperature for 24 hours. The reaction was monitored by TLC. After the reaction, the crude product was purified by silica gel column chromatography, eluted with petroleum ether / acetone / dichloromethane (8:1:1), and 42.7 mg of colorless oily liquid was obtained, with a yield of 65%. A mixed solution of petroleum ether / acetone / dichloromethane (4:1:1) was used as the developing solvent, R f =0.41, I-17 was prepared, and its chemical structure is as follows:

[0161]

[0162] 1 H NMR (400MHz, CDCl3) δ7.86 (d, J=8.0Hz, 1H), 7.72 (d, J=7.6Hz, 1H), 7.67 (td, J=8.0, 1.2Hz, 1H), 7.59-7.55 (m, 1H), 7.3 4-7.28 (m, 1H), 5.19 (s, 1H), 3.65 (s, 3H), 3.32-3.17 (m, 2H), 2.29 (t, J=7.2Hz, 2H), 1.89 (s, 3H), 1.80 (p, J=7.1Hz, 2H). 13 C NMR (101MHz, CDCl3) δ173.7, 170.4, 140.6, 134.0, 133.9, 130.3, 125.7, 120.9, 65.8, 51.8, 39.4, 31.3, 26.3, 24.5.HRMS (ESI): calculated for C 14 H 19 N2O5S[M+H] + :327.1009, found:327.1007.HPLC:Daicel Chiralcel OD-H, n-hexane / isopropanol=90 / 10, flow rate 1.0 mL / min, λ=210 nm, t R (minor) = 36.194min, t R (major)=38.516min, 96.5: 3.5er.[α] 25 D =-35.6°(c=0.93in CHCl3).

[0163] Example 18: Preparation of (S)-(3-methyl-1,1-dioxo-2,3-dihydrophenylpropano[d]isothiazole-3-carbonyl)glycine methyl ester I-18:

[0164] In a glove box, ethylene glycol dimethyl ether nickel bromide (10 mol%, 6.2 mg), (4S, 4′S)-2,2′-cyclopentylidenebis[4,5-dihydro-4-phenyloxazole] (12 mol%, 8.7 mg), [4,4′-di-tert-butyl-2,2′-bipyridine N1, N1′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl N]phenyl -C] iridium (III) hexafluorophosphate (1 mol%, 2.2 mg), then, (1,1-dioxo-2,3-dihydrophenylpropano[d]isothiazole-3-carbonyl) glycine methyl ester (0.20 mmol, 56.9 mg), hexafluoroisopropanol (0.32 mL), tert-butyl peroxide (5.0 eq., 0.18 mL) were added in sequence, 40 W blue light was irradiated, and the reaction was reacted at room temperature for 24 hours. The reaction was monitored by TLC. After the reaction, the crude product was purified by silica gel column chromatography, eluted with petroleum ether / acetone / dichloromethane (6:1:1), and 40.5 mg of colorless oily liquid was obtained, with a yield of 68%. A mixed solution of petroleum ether / acetone / dichloromethane (4:1:1) was used as the developing solvent, R f =0.43, I-18 was prepared, and its chemical structure is as follows:

[0165]

[0166] 1 H NMR (400MHz, CDCl3) δ7.84 (d, J=8.0Hz, 1H), 7.74-7.65 (m, 3H), 7.60 (t, J=7.6Hz, 1H), 5.78 ( s, 1H), 4.12 (dd, J=18.0, 6.4Hz, 1H), 3.81 (dd, J=18.0, 4.8Hz, 1H), 3.70 (s, 3H), 1.91 (s, 3H). 13 C NMR (101MHz, CDCl3) δ171.1, 169.9, 140.0, 134.0, 133.8, 130.3, 125.5, 121.0, 65.7, 52.5, 41.6, 26.2.HRMS (ESI): calculated for C 12 H 15 N2O5S[M+H] + : 299.0696, found: 299.0698.HPLC: Daicel Chiralcel OD-H, n-hexane / isopropanol = 90 / 10, flow rate 1.0 mL / min, λ = 210 nm, t R (minor) = 21.245min, t R(major)=31.181min, 94:6er.[α] 25 D =-51.5°(c=1.00inCHCl3).

[0167] Example 19: Preparation of (R)-3-methyl-2,3-dihydrobenzo[d]isothiazole-3-carboxylic acid (2-(4-([1,1′-diphenyl]-4-yl)-4-oxobutyrylamino))ethyl ester-1,1-dioxide I-19:

[0168] In a glove box, ethylene glycol dimethyl ether nickel bromide (10 mol%, 6.2 mg), (3aS, 3a'S, 8aR, 8a'R)-2,2'-isopropylidenebis(3a,8a-dihydro-8H-indeno[1,2-d]oxazole) (12 mol%, 8.6 mg), [4,4'-di-tert-butyl-2,2'-bipyridine N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl N]phenyl -C] iridium (III) hexafluorophosphate (1 mol%, 2.2 mg), then, 2,3-dihydrobenzo[d]isothiazole-3-carboxylic acid (2-(4-([1,1′-diphenyl]-4-yl)-4-oxobutyrylamino)) ethyl ester (0.20 mmol, 98.5 mg), hexafluoroisopropanol (0.32 mL), tert-butyl peroxide (2.0 eq., 0.072 mL) were added in sequence, 40 W blue light was irradiated, and the reaction was reacted at room temperature for 24 hours. The reaction was monitored by TLC. After the reaction, the crude product was purified by silica gel column chromatography, eluted with petroleum ether / acetone / dichloromethane (6:1:1), and 40.4 mg of colorless oily liquid was obtained, with a yield of 40%. A mixed solution of petroleum ether / acetone / dichloromethane (2:1:1) was used as the developing solvent, R f =0.37, I-19 was prepared, and its chemical structure is as follows:

[0169]

[0170] 1H NMR (400MHz, CDCl3) δ8.03 (d, J=8.0Hz, 2H), 7.80 (d, J=7.6Hz, 1H), 7.79-7.54 (m, 7H), 7.48-7.38 (m, 3H), 6.77 (t, J=6.0Hz, 1H), 6.71 (s, 1H), 4. 30-4.25(m, 1H), 4.16-4.11(m, 1H), 3.72-3.65(m, 1H), 3.54-3.46(m, 1H ), 3.34-3.25(m, 2H), 2.73-2.65(m, 1H), 2.57-2.50(m, 1H), 1.89(s, 3H). 13 C NMR (101MHz, CDCl3) δ199.7, 173.2, 170.6, 146.3, 139.9, 138.7, 135.2, 134.9, 133.8, 130.5, 129.1, 12 8.9, 128.4, 127.44, 127.42, 124.6, 121.5, 65.5, 65.4, 38.3, 34.3, 30.4, 26.1.HRMS (ESI): calculated for C 27 H 27 N2O6S[M+H] + :507.1584,found:507.1584.HPLC:Daicel Chiralcel OD-H,n-hexane / isopropanol=80 / 20,flow rate 1.0 mL / min,λ=210 nm,t R (minor) = 41.387min, t R (major)=51.991min,97.5:2.5er.[α] 25 D =-20.6°(c=1.00in CHCl3).

[0171] Example 20: Preparation of (R)-3-methyl-2,3-dihydrobenzo[d]isothiazole-3-carboxylic acid (3-(4-(N,N-dipropylsulfonamido)benzamido))ethyl ester-1,1-dioxide I-20:

[0172] In a glove box, ethylene glycol dimethyl ether nickel bromide (10 mol%, 6.2 mg), (3aS, 3a'S, 8aR, 8a'R)-2,2'-isopropylidenebis(3a,8a-dihydro-8H-indeno[1,2-d]oxazole) (12 mol%, 8.6 mg), [4,4'-di-tert-butyl-2,2'-bipyridine N1,N1']bis[3,5-difluoro-2 -[5-(trifluoromethyl)-2-pyridyl N]phenyl-C]iridium (III) hexafluorophosphate (1 mol%, 2.2 mg), then, 2,3-dihydrobenzo[d]isothiazole-3-carboxylic acid (3-(4-(N,N-dipropylsulfonamido)benzamido))ethyl ester-1,1-dioxide (0.20 mmol, 104.7 mg), hexafluoroisopropanol (0.32 mL), tert-butyl peroxide (2.0 eq., 0.072 mL) were added in sequence, 40W blue light was irradiated, and the reaction was reacted at room temperature for 24 hours, and the reaction was monitored by TLC. After the reaction, the crude product was purified by silica gel column chromatography, eluted with petroleum ether / acetone / dichloromethane (8:1:1), and 57.6 mg of white solid was obtained, with a yield of 54%. A mixed solution of petroleum ether / acetone / dichloromethane (3:1:1) was used as the developing solvent, R f =0.47, I-20 was prepared, and its chemical structure is as follows:

[0173]

[0174] 1 H NMR (400MHz, CDCl3) δ7.85 (d, J=8.4Hz, 2H), 7.78 (d, J=8.4Hz, 2H), 7.71 (d, J=7.6Hz, 1H), 7.63-7.62 (m, 2H), 7.57-7.54 (m, 1H), 7.28 (t, J=6. 0Hz, 1H), 6.03 (s, 1H), 4.31 (t, J=5.2Hz, 2H), 3.74-3.69 (m, 2H), 3.09 (t, J=7.6Hz, 4H), 1.87 (s, 3H), 1.59-1.50 (m, 4H), 0.87 (t, J=7.2Hz, 6H). 13 C NMR (101MHz, CDCl3) δ170.5, 166.5, 142.9, 138.8, 137.4, 134.7, 134.0, 130.6, 128.1, 127.2, 124.7, 121.2, 65.7, 65.3, 50.1, 38.8, 25.8, 22.1, 11.3.HRMS (ESI): calculated for C 24 H 32 N3O7S2[M+H]+ : 538.1676, found: 538.1676. HPLC: Daicel Chiralcel OD-H, n-hexane / isopropanol = 80 / 20, flow rate 1.0 mL / min, λ = 210 nm, t R (minor) = 18.976min, t R (major)=23.394min,95.5:4.5er.[α] 25 D =-36.7°(c=1.00in CHCl3).

[0175] Example 21: Preparation of (S)-N-(1-(pyridin-2-yl)ethyl)pivalamide I-21:

[0176] In a glove box, nickel acetylacetonate (5 mol%, 1.3 mg), (3aS, 8aR)-2-(2-((3aR, 8aR, 3a-8H-dihydro-8H-indeno[1,2-d]oxazol-2-yl)-1,3-bis(4-fluorophenyl)propan-2-yl)-3a, 8a-dihydro-8H-indeno[1,2-d]oxazole (6 mol%, 3.3 mg), [4,4′-bis-tert-butyl-2,2′-bipyridine N1, N1′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl N]phenyl-C]iridium(III)hexafluorophosphate (1 mL) were added to a dried 1.5 mL clear glass vial. ol%, 1.1mg), and then N-(1-(pyridin-2-yl)methyl)pivalamide (0.10mmol, 19.2mg), hexafluoroisopropanol (0.08mL), tert-butyl peroxide (8.0eq., 0.144mL), sodium tetraphenylborate (0.2eq., 6.8mg) were added in sequence, 40W blue light was irradiated, and the reaction was carried out at -20℃ for 24 hours. The reaction was monitored by TLC. After the reaction, the crude product was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (3:1), and 13.1mg of white solid was obtained, with a yield of 64%. A mixed solution of petroleum ether / ethyl acetate (1:1) was used as the developing solvent, R f =0.65, I-21 was prepared, and its chemical structure is as follows:

[0177]

[0178] 1H NMR (400MHz, CDCl3) δ8.53 (d, J=4.8Hz, 1H), 7.64 (td, J=7.8, 1.4Hz, 1H), 7.22 (d, J=7. 6Hz, 1H), 7.19-7.16 (m, 2H), 5.09 (p, J=6.9Hz, 1H), 1.44 (d, J=6.8Hz, 3H), 1.22 (s, 9H). 13 C NMR (101MHz, CDCl3) δ177.9, 161.5, 149.2, 136.9, 122.3, 121.7, 49.7, 38.8, 27.7, 22.9.HRMS (ESI): calculated for C 12 H 19 N2O[M+H] + : 207.1492, found: 207.1492. HPLC: Daicel Chiralpak IC, n-hexane / isopropanol = 90 / 10, flow rate 1.0 mL / min, λ = 254 nm, t R (minor) = 12.337min, t R (major)=14.224min,90.5:9.5er.[α] 25 D =-79.4°(c=1.00in CHCl3).

[0179] Example 22: Preparation of (S)-2,2-dimethyl-N-(1-(pyridin-2-yl)ethyl)pentanamide I-22:

[0180] In a glove box, nickel acetylacetonate (5 mol%, 1.3 mg), (3aS, 8aR)-2-(2-((3aR, 8aR, 3a-8H-dihydro-8H-indeno[1,2-d]oxazol-2-yl)-1,3-bis(4-fluorophenyl)propan-2-yl)-3a, 8a-dihydro-8H-indeno[1,2-d]oxazole (6 mol%, 3.3 mg), [4,4′-bis-tert-butyl-2,2′-bipyridine N1, N1′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl N]phenyl-C]iridium(III)hexafluorophosphate (1 mol%, 3.3 mg) were added to a dried 1.5 mL clear glass vial. 1.1mg), then add 2,2-dimethyl-N-(1-(pyridin-2-yl)methyl)pentanamide (0.10mmol, 22.0mg), hexafluoroisopropanol (0.08mL), tert-butyl peroxide (8.0eq., 0.144mL), sodium tetraphenylborate (0.2eq., 6.8mg), 40W blue light irradiation, react at -20℃ for 24 hours, and monitor the reaction by TLC. After the reaction, the crude product was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (15:1), and 12.5mg of white solid was obtained, with a yield of 53%. A mixed solution of petroleum ether / ethyl acetate (6:1) was used as the developing solvent, R f =0.25, I-22 was prepared, and its chemical structure is as follows:

[0181]

[0182] 1 H NMR (400MHz, CDCl3) δ8.53 (d, J=4.4Hz, 1H), 7.65 (td, J=7.6, 2.0Hz, 1H), 7.23 (d, J=8.0Hz, 1H), 7.19-7.16 (m, 1H), 7.14 -7.13 (m, 1H), 5.10 (p, J=6.8Hz, 1H), 1.54-1.47 (m, 2H), 1.44 (d, J=6.4Hz, 3H), 1.29-1.18 (m, 8H), 0.86 (t, J=7.2Hz, 3H). 13 C NMR (101MHz, CDCl3) δ177.3, 161.5, 149.1, 137.0, 122.4, 121.7, 49.7, 43.9, 42.3, 25.7, 25.4, 22.8, 18.2, 14.7.HRMS (ESI): calculated for C 14 H 23 N2O[M+H] +: 235.1805, found: 235.1802. HPLC: Daicel Chiralpak IC, n-hexane / isopropanol = 95 / 5, flow rate 1.0 mL / min, λ = 254 nm, t R (minor) = 15.303min, t R (major)=16.268min, 92.5: 7.5er.[α] 25 D =-9.0°(c=0.12, CHCl3).

[0183] Example 23: Preparation of (S)-N-(1-(quinolin-2-yl)ethyl)pivalamide I-23:

[0184] In a glove box, nickel acetylacetonate (5 mol%, 1.3 mg), (3aS, 8aR)-2-(2-((3aR, 8aR, 3a-8H-dihydro-8H-indeno[1,2-d]oxazol-2-yl)-1,3-bis(4-fluorophenyl)propan-2-yl)-3a, 8a-dihydro-8H-indeno[1,2-d]oxazole (6 mol%, 3.3 mg), [4,4′-bis-tert-butyl-2,2′-bipyridine N1,N1′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl N]phenyl-C]iridium(III)hexafluorophosphate (1 mol%) were added to a dried 1.5 mL clear glass vial. 1%, 1.1mg), then N-(1-(quinolin-2-yl)methyl)pivalamide (0.10mmol, 24.2mg), hexafluoroisopropanol (0.08mL), tert-butyl peroxide (6.0eq., 0.108mL), sodium tetraphenylborate (0.2eq., 6.8mg) were added in sequence, 40W blue light was irradiated, and the reaction was carried out at -20℃ for 24 hours. The reaction was monitored by TLC. After the reaction, the crude product was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (10:1), and 12.1mg of white solid was obtained, with a yield of 47%. A mixed solution of petroleum ether / ethyl acetate (3:1) was used as the developing solvent, R f =0.48, I-23 was prepared, and its chemical structure is as follows:

[0185]

[0186] 1H NMR (400MHz, CDCl3) δ8.16 (d, J=8.4Hz, 1H), 8.08 (d, J=7.6, Hz, 1H), 7.83-7.81 (m, 2H), 7.73 (t, J=7.6Hz, 1 H), 7.55 (t, J=7.6Hz, 1H), 7.36 (d, J=8.4Hz, 1H), 5.23 (p, J=6.8Hz, 1H), 1.55 (d, J=6.8Hz, 3H), 1.29 (s, 9H). 13 C NMR (101MHz, CDCl3) δ178.2, 161.4, 147.0, 137.4, 130.0, 128.9, 127.8, 127.5, 126.6, 119.8, 50.0, 39.0, 27.7, 22.6.HRMS (ESI): calculated for C 16 H 21 N2O[M+H] + : 257.1648, found: 257.1648. HPLC: Daicel Chiralpak ID, n-hexane / isopropanol = 95 / 5, flow rate 1.0 mL / min, λ = 210 nm, t R (major) = 12.416min, t R (minor)=16.292min,91:9er.[α] 25 D =-16.9°(c=0.17, CHCl3).

[0187] Example 24: Preparation of (S)-N-(1-(4-methoxypyridin-2-yl)ethyl)pivalamide I-24:

[0188] In a glove box, nickel acetylacetonate (5 mol%, 1.3 mg), (3aS, 8aR)-2-(2-((3aR, 8aR, 3a-8H-dihydro-8H-indeno[1,2-d]oxazol-2-yl)-1,3-bis(4-fluorophenyl)propan-2-yl)-3a, 8a-dihydro-8H-indeno[1,2-d]oxazole (6 mol%, 3.3 mg), [4,4′-bis-tert-butyl-2,2′-bipyridine N1, N1′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl N]phenyl-C]iridium(III)hexafluorophosphate (1 mol%) were added to a dried 1.5 mL clear glass vial. , 1.1 mg), then N-(1-(4-methoxypyridin-2-yl)methyl)pivalamide (0.10 mmol, 22.2 mg), hexafluoroisopropanol (0.08 mL), tert-butyl peroxide (6.0 eq., 0.108 mL), sodium tetraphenylborate (0.20 eq., 6.8 mg) were added in sequence, 40 W blue light was irradiated, and the reaction was carried out at -20 ° C for 24 hours. The reaction was monitored by TLC. After the reaction, the crude product was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (3:1), and 15.0 mg of white solid was obtained, with a yield of 64%. A mixed solution of petroleum ether / ethyl acetate (1:1) was used as a developing solvent, R f =0.33, I-24 was prepared, and its chemical structure is as follows:

[0189]

[0190] 1 H NMR (400MHz, CDCl3) δ8.35 (d, J=6.0Hz, 1H), 7.23 (br, 1H), 6.79-6.76 (m, 2H), 5.05 (p, J=6.8Hz, 1H), 3.87 (s, 3H), 1.48 (d, J=6.8Hz, 3H), 1.22 (s, 9H). 13 C NMR (101MHz, CDCl3) δ178.0, 166.8, 163.1, 149.8, 109.1, 107.5, 55.5, 49.9, 38.9, 27.7, 22.6.HRMS (ESI): calculated for C 13 H 21 N2O2[M+H] + : 237.1598, found: 237.1598.HPLC: DaicelChiralpak IC, n-hexane / isopropanol=90 / 10, flow rate 1.0 mL / min, λ=205 nm, t R (minor) = 13.280min, t R(major)=20.948min, 87:13er.[α] 25 D =439.2°(c=0.24, CHCl3).

[0191] Example 25: Preparation of (S)-N-(1-(4-(4-cyanophenyl)pyridin-2-yl)ethyl)pivalamide I-25: In a glove box, to a dry 1.5 mL clear glass vial were added nickel acetylacetonate (5 mol%, 1.3 mg), (3aS, 8aR)-2-(2-((3aR, 8aR, 3a-8H-dihydro-8H-indeno[1,2-d]oxazol-2-yl)-1,3-bis(4-fluorophenyl)propan-2-yl)-3a, 8a-dihydro-8H-indeno[1,2-d]oxazole (6 mol%, 3.3 mg), [4,4′-bis-tert-butyl-2,2′-bipyridine N1, N1′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl N ]phenyl-C]iridium hexafluorophosphate (iii) (1 mol%, 1.1 mg), and then N-(1-(4-(4-cyanophenyl)pyridin-2-yl)methyl)pivalamide (0.10 mmol, 29.3 mg), hexafluoroisopropanol (0.08 mL), tert-butyl peroxide (8.0 eq., 0.144 mL), sodium tetraphenylborate (0.2 eq., 6.8 mg) were added in sequence, 40 W blue light was irradiated, and the reaction was carried out at -20 ° C for 24 hours. The reaction was monitored by TLC. After the reaction, the crude product was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (3:1), and 10.3 mg of white solid was obtained, with a yield of 34%. A mixed solution of petroleum ether / ethyl acetate (1:1) was used as the developing solvent, R f =0.52, I-25 was prepared, and its chemical structure is as follows:

[0192]

[0193] 1 H NMR (400MHz, CDCl3) δ8.65 (d, J=4.8Hz, 1H), 7.80-7.71 (m, 4H), 7.44 (s, 1H), 7.40 (dd, J=5.2, 1.6Hz, 1H), 7.07 (d, J=6.4Hz, 1H), 5.20 (p, J=6.8Hz, 1H), 1.50 (d, J=6.8Hz, 3H), 1.23 (s, 9H). 13C NMR (101MHz, CDCl3) δ178.0, 162.7, 150.0, 147.5, 142.7, 133.1, 128.0, 120.5, 119.7, 118.5, 113.1, 49.9, 38.9, 27.7, 22.8.HRMS (ESI): calculated for C 19 H 22 N3O[M+H] + : 308.1757, found: 308.1758.HPLC: Daicel Chiralpak IC, n-hexane / isopropanol=80 / 20, flow rate 1.0 mL / min, λ=254 nm, t R (minor) = 22.106min, t R (major)=37.880min,88:12er.[α] 25 D =-2.0°(c=0.12, CHCl3).

[0194] Example 26: Preparation of (R)-3-ethyl-2,3-dihydrobenzo[d]isothiazole-3-carboxylic acid methyl ester-1,1-dioxide I-26:

[0195] In a glove box, ethylene glycol dimethyl ether nickel bromide (10 mol%, 6.2 mg), (4R, 4'R)-2,2'-cyclopropylidene[4,5-dihydro-4-phenyloxazole] (12 mol%, 8.0 mg), [4,4'-di-tert-butyl-2,2'-bipyridine N1, N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl N]benzene were added to a dry 1.5 mL clear glass vial. 1-[(C-]-]iridium(III)hexafluorophosphate (1mol%, 2.2mg), then, 2,3-dihydrobenzo[d]isothiazole-3-carboxylic acid methyl ester 1,1-dioxide (0.20mmol, 45.4mg), hexafluoroisopropanol (0.32mL), di-tert-amyl peroxide (5.0eq., 0.213mL) were added in sequence, 40W blue light was irradiated, and the reaction was reacted at room temperature for 24 hours. The reaction was monitored by TLC. After the reaction, the crude product was purified by silica gel column chromatography, eluted with petroleum ether / acetone / dichloromethane (8:1:1), and 27.8mg of white solid was obtained, with a yield of 54%. A mixed solution of petroleum ether / acetone / dichloromethane = 4 / 1 / 1 was used as the developing solvent, R f =0.53, I-26 was prepared, and its chemical structure is as follows:

[0196]

[0197] 1H NMR (400MHz, CDCl3) δ7.75 (d, J=7.6Hz, 1H), 7.71 (d, J=7.6Hz, 1H), 7.66 (td, J=7.2, 0.9Hz, 1H), 7.60 -7.56 (m, 1H), 5.71 (s, 1H), 3.88 (s, 3H), 2.30-2.21 (m, 1H), 2.09-2.00 (m, 1H), 0.96 (t, J=7.2Hz, 3H). 13 C NMR (101MHz, CDCl3) δ170.8, 138.0, 135.5, 133.6, 130.6, 125.2, 121.6, 70.1, 54.2, 33.9, 9.0.HRMS (ESI): calculated for C 11 H 14 NO4S[M+H] + :256.0638,found:256.0635.HPLC:Daicel Chiralcel OD-H,n-hexane / isopropanol=90 / 10,flow rate 1.0mL / min.λ=210nm,t R (minor) = 14.763min, t R (major)=20.761min,95:5er.[α] 25 D = +33.4° (c = 1.00 in CHCl3).

[0198] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solution of the present invention can be modified or replaced by equivalents without departing from the purpose and scope of the technical solution, which should be included in the scope of the claims of the present invention.

Claims

1. An optically active amine derivative, characterized in that: The amine derivative has a structure shown in the following general formula (I): Dashed lines indicate bonding or non-bonding; Each Z is independently selected from CR 1 or N; R is selected from methyl or ethyl; Y 1 Select from H or Y 2 Select from H or Y 3 Select from H or X is selected from O, S or NH; represents the connection site; C* represents chiral carbon, including R and S configurations; Each of the R 1 are independently selected from H, halogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 alkoxy, cyano, substituted alkynyl, substituted alkenyl, substituted or unsubstituted aryl having 5 to 40 ring atoms, substituted or unsubstituted heteroaryl having 5 to 40 ring atoms; the adjacent R 1 They may or may not form a ring; The R 2 is selected from substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 ester, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 amide, substituted or unsubstituted C1-C10 sulfonamide, substituted alkynyl, substituted alkenyl, substituted or unsubstituted aryl having 5 to 40 ring atoms, or one of the following structures: The R 3 is selected from substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 acyloxy, substituted or unsubstituted C1-C10 alkoxy, and substituted or unsubstituted C1-C10 amino.

2. The optically active amine derivative according to claim 1, characterized in that: The optically active derivatives include 3-alkyl-3-quaternary carbon benzsulfonam derivatives, and the chemical structure of the 3-alkyl-3-quaternary carbon benzsulfonam derivatives is generally represented by (II) or (III) or (IV) or as shown below: Z are independently selected from CR 1 or N; X is selected from O, S or NH; R is selected from methyl or ethyl; R 1 As shown in claim 1, comprising H, 5-fluoro, 6-fluoro, 7-fluoro, 5-chloro, 6-chloro, 7-chloro, 5-phenyl, 5-p-methoxyphenyl, 5-p-chlorophenyl, 5-p-cyanophenyl, 5-trifluoromethoxy, 5-trifluoromethyl, 5-methyl, 5-ethyl, 5-propyl, 5-butyl, 5-tert-butyl, 5-methoxy, 5-ethoxy, 5-cyano, 5-(2-phenyl)alkynyl, 5-(2-phenyl)alkenyl, 1-naphthyl, 2-naphthyl or benzofuran; R 2 As shown in claim 1, it includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, phenyl, p-methoxyphenyl or one of the following structures:

3. The optically active amine derivative according to claim 1, characterized in that: The optically active amine derivatives include 2-aminoethylpyridine derivatives, and the chemical structure of the 2-aminoethylpyridine derivatives is shown in the following formula (V): Z are independently selected from CR 1 or N; R 1 As shown in claim 1, comprising H, 4-chloro, 3-chloro, 5-chloro, 6-chloro, 6-fluoro, 3-bromo, 5-trifluoromethyl, 4-methoxy, 6-methoxy, 4-phenyl, 4-(4-cyano)phenyl, 4-(4-tert-butyl)phenyl, 4-(4-butyl)phenyl, 4-(4-methoxycarbonyl)phenyl, 4-(4-phenylaminocarbonyl)phenyl, 2-quinolyl or 3-isoquinolyl; R 3 As shown in claim 1, it includes methyl, tert-butyl, tert-butyloxycarbonyl, 1,1-dimethylbutyl, and 1,1-dimethyl-4-methoxycarbonylbutyl.

4. Use of the optically active amine derivatives according to any one of claims 1 to 3 in antiviral, anti-inflammatory, anti-tumor and other drugs.

5. A free radical type C(sp 3 )-H asymmetric alkylation synthesis method, characterized in that, The synthetic route of the method is as follows: Among them, the dashed line, Z, R, C*, Y 1 , Y 2 , Y 3 The definition is the same as that of claims 1 to 3.

6. The synthesis method according to claim 5, characterized in that The steps include: In an argon or nitrogen atmosphere, a nickel salt catalyst, a chiral ligand, a photocatalyst, an amine substrate and a solvent are mixed to prepare a first reaction mixture; a peroxide alkyl source is added to the first reaction mixture to prepare a second reaction mixture; and the second reaction mixture is subjected to a photocatalytic reaction.

7. The synthesis method according to claim 5, characterized in that Satisfy one or more of the following (1) to (6): (1) The nickel salt includes one or more of ethylene glycol dimethyl ether nickel bromide, ethylene glycol dimethyl ether nickel chloride, bis(triphenylphosphine)nickel chloride, bis(triphenylphosphine)nickel bromide, tetrapyridine nickel chloride, nickel chloride, nickel bromide, nickel iodide, nickel acetylacetonate, nickel trifluoromethanesulfonate, bis-(1,5-cyclooctadiene)nickel, and nickel acetate; (2) The chiral ligands include (3aS, 3a'S, 8aR, 8a'R)-2,2'-isopropylidenebis(3a,8a-dihydro-8H-indeno[1,2-d]oxazole), (3aR, 3a'R, 8aS, 8a'S)-2,2'-isopropylidenebis(3a,8a-dihydro-8H-indeno[1,2-d]oxazole), (3aS, 3a'S, 8aR, 8a'R)-2,2'-cyclopentylenebis(3a,8a- dihydro-8H-indeno[1,2-d]oxazole), (3aR,3a'R,8aS,8a'S)-2,2'-cyclopentylidenebis(3a,8a-dihydro-8H-indeno[1,2-d]oxazole), (3aS,3a'S,8aR,8a'R)-2,2'-cyclopropylenebis(3a,8a-dihydro-8H-indeno[1,2-d]oxazole), (3aR,3a'R,8aS,8a'S)-2,2'-cyclopropylene bis(3a,8a-dihydro-8H-indeno[1,2-d]oxazole), (3aS,3a'S,8aR,8a'R)-2,2'-(1,3-diarylpropane-2,2-diyl)bis(3a,8a-dihydro-8H-indeno[1,2-d]oxazole), (3aR,3a'R,8aS,8a'S)-2,2'-(1,3-diarylpropane-2,2-diyl)bis(3a,8a-dihydro-8H-indeno[1,2-d]oxazole 1,2-d] oxazole), (4S,4′S)-2,2′-cyclopentylidenebis[4,5-dihydro-4-phenyloxazole], (4R,4′R)-2,2′-cyclopentylidenebis[4,5-dihydro-4-phenyloxazole], (4R,4′R)-2,2′-cyclopropylidene[4,5-dihydro-4-phenyloxazole] and (4S,4′S)-2,2′-cyclopropylidene[4,5-dihydro-4-phenyloxazole]; (3) The photocatalyst comprises [4,4′-di-tert-butyl-2,2′-bipyridine N1, N1′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl N]phenyl-C]iridium(III) hexafluorophosphate; (4) The solvent includes hexafluoroisopropanol or trifluoroethanol; (5) the alkyl source comprises one of tert-butyl peroxide, diisopropylbenzene peroxide and di-tert-amyl peroxide; (6) The additive includes sodium tetraphenylborate.

8. The preparation method according to claim 5 or 6, characterized in that: The general structural formula of the amine substrate is shown in the following formula (VI): Dashed Line, Z, Y 1 , Y 2 , Y 3 The definition is the same as that of claims 1 to 3.

9. The preparation method according to claim 7, characterized in that: Satisfy one or more of the following (1) to (10): (1) The molar percentage of the nickel salt catalyst and the amine substrate is 5% to 20%; (2) The molar percentage of the photocatalyst and the amine substrate is 0.8% to 1.5%; (3) The molar percentage of the chiral ligand and the amine substrate is 6% to 24%; (4) The molar ratio of the nickel salt catalyst to the chiral ligand is 1:(1.2-2.0); (5) The molar ratio of the nickel salt catalyst to the photocatalyst is (5-20):1; (6) The molar equivalent of the alkyl source and the amine substrate is 2.0 eq. to 12.0 eq.; (7) The molar equivalent of the additive to the amine substrate is 0.2 eq. to 1.0 eq.; (8) The light source for the photocatalytic reaction is blue light; (9) The reaction temperature of the photocatalytic reaction is -25°C to 30°C; (10) The reaction time of the photocatalytic reaction is 24h to 72h.

10. Application of the asymmetric alkylation synthesis method of amine derivatives according to any one of claims 5 to 9 in the field of late derivatization and modification of natural products or candidate drugs.

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