HFIP-assisted C (sp3)-H bond direct methylation method and application thereof

Abstract

The invention relates to a light nickel concerted catalysis hexafluoroisopropanol assisted C (sp3)-H bond direct methylation method and application thereof in late methylation modification of complex drug molecules, and belongs to the field of drug synthesis chemistry, and the method comprises the following synthesis steps: taking nickel salt as a catalyst, iridium salt as a photocatalyst and tert-butyl peroxide as a methyl source, and carrying out a one-step reaction to obtain a methylated C (sp3)-H bond; hFIP (hexafluoroisopropanol) is used as a solvent, and N / O atom ortho-position C (sp3)-H bond direct methylation is carried out on derivatives such as amine, ether, alcohol, amino acid and dipeptide at room temperature. In addition, by applying the method, direct later-stage methylation modification can be performed on complex drug molecules.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical synthesis chemistry, and particularly relates to a photo-nickel synergistic catalytic HFIP-assisted C(sp 3 )-H bond direct methylation method and its methylation application on complex drug molecules. Background Art

[0002] Benzylamine and benzyl alcohol skeletons are very common in lead compounds, drug molecules and natural products. Drugs containing benzylamine skeletons include the analgesic flupirtine1, the targeted drug for advanced gastric cancer apatinib2, the ATP-competitive inhibitor of VEGFR motesanib3, the anti-AIDS drugs dolutegravir4 and raltegravir5, and the anti-epileptic drug lacosamide6. Drugs containing benzyl alcohol skeletons include the adrenergic receptor agonist pirburot7, the vitamin pyridoxal8, the broad-spectrum antibacterial drug chloramphenicol9, the antimalarial drug mefloquine10, the serotonin reuptake inhibitor fluoxetine11, and the antihistamine carbinoxamine12. This shows the importance and prevalence of this type of skeleton.

[0003]

[0004] Methyl is one of the most common functional groups in biologically active molecules and is also the core pharmacophore of many drug molecules. Based on the "magical methylation effect", methyl is often introduced during the modification and optimization of candidate drugs to improve the biological activity and physicochemical properties of drug molecules, including improving half-life, enhancing selectivity, increasing binding affinity, and drug efficacy conversion.

[0005] At present, there are two main approaches to methylation modification: one is to adopt a de novo synthesis strategy, and the other is direct CH methylation. De novo synthesis usually has problems such as long synthesis route, long cycle, high cost, and complex process, so direct CH methylation is more advantageous. At present, various types of C(sp 3 )-H bonds, such as hydrogen extraction under strong base conditions, palladium / rhodium-catalyzed C(sp 3 )-H methylation, oxidation of C(sp 3 )-H methylation, and free radical C(sp 3 )H methylation, etc. However, these methods have problems such as poor functional group tolerance, narrow substrate range, use of noble metal catalysis, multi-step reactions, involvement of organic metal reagents, ultra-low temperature conditions, and complex operations.

[0006] Therefore, in view of the problems existing in the previous methods, a HFIP-assisted C(sp 3 The direct methylation method of )-H bonds has important research significance. Summary of the invention

[0007] In view of this, the object of the present invention is to provide a photo-nickel synergistic catalytic HFIP-assisted C (sp 3 )-H bond direct methylation method, and the application of this method in the later methylation modification of complex drug molecules.

[0008] In order to achieve the above object, the present invention provides the following technical solutions:

[0009] The first aspect of the present invention provides a HFIP booster C(sp 3 )-H bond direct methylation synthesis method, characterized in that the synthesis route of the method is as follows:

[0010]

[0011] Wherein, in the general structural formula I of the synthesized α-methylated product, X is N, O or S; the dotted line indicates bonding or non-bonding;

[0012] R 1 is selected from substituted or unsubstituted aryl having 5 to 40 ring atoms, substituted or unsubstituted heteroaryl having 5 to 40 ring atoms, substituted or unsubstituted C1-C10 alkyl, substituted acyl, substituted alkoxycarbonyl, substituted aryloxycarbonyl, substituted alkylaminocarbonyl, substituted arylaminocarbonyl, substituted alkenyl or substituted alkynyl;

[0013] R 2 is selected from H, substituted or unsubstituted C1-C10 alkyl, substituted acyl, substituted alkylaminocarbonyl, substituted alkoxycarbonyl, substituted or unsubstituted aryl having 5 to 40 ring atoms, or substituted or unsubstituted heteroaryl having 5 to 40 ring atoms;

[0014] R 3 Absent or selected from H, substituted acyl, substituted ester, substituted amide or substituted sulfonamide;

[0015] R 4 is selected from H, D, a substituted or unsubstituted C1-C5 alkyl group, a substituted alkoxycarbonyl group, a substituted alkylaminocarbonyl group or a substituted or unsubstituted aryl group having 5 to 40 ring atoms.

[0016] The method comprises the following steps:

[0017] In an argon or nitrogen atmosphere, a nickel salt catalyst, a ligand, a photocatalyst, a substrate to be methylated, an additive and a solvent are mixed to prepare a first reaction mixture; a methyl 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.

[0018] In some embodiments, the nickel salt catalyst includes one or more of ethylene glycol dimethyl ether nickel chloride, ethylene glycol dimethyl ether nickel bromide, nickel chloride, nickel bromide, nickel acetylacetonate and tetrapyridine nickel chloride.

[0019] In some embodiments, the ligand includes no addition, 2,9-dimethyl-1,10-phenanthroline, 1,10-phenanthroline, tris(2-pyridylmethyl)amine, 1,3-bi(4-pyridyl)propane, terpyridine, 4,4'-dimethyl-2,2'-bipyridine, 6,6'-dimethyl-2,2'-bipyridine, 4,4'-di-tert-butyl-2,2'-bipyridine, 1,2-bis(diphenylphosphino)ethane and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine. One or more.

[0020] 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.

[0021] In some embodiments, the methyl source includes one or more of tert-butyl peroxide and dicumyl peroxide.

[0022] In some embodiments, the solvent includes one or more of hexafluoroisopropanol, trifluoroethanol, and dimethyl sulfoxide.

[0023] In some embodiments, the additive includes one or more of pyridine and substituted pyridine derivatives thereof.

[0024] In some embodiments, the general structural formula of the substrate to be methylated is shown in the following formula (II):

[0025]

[0026] Dashed line, X, R 1 , R 2 , R 3 , R 4 The definition is the same as that of claim 1.

[0027] In some embodiments, the molar percentage of the nickel salt catalyst and the substrate to be methylated is 5% to 20%.

[0028] In some embodiments, the molar percentage of the photocatalyst and the substrate to be methylated is 0.5% to 2%.

[0029] In some embodiments, the molar percentage of the ligand and the substrate to be methylated is 6% to 24%.

[0030] In some embodiments, the molar ratio of the nickel salt catalyst to the photocatalyst is (5-20):1.

[0031] In some embodiments, the molar volume ratio of the substrate to be methylated and the solvent is 1 mov:(0.4-1.2)L.

[0032] In some embodiments, the molar ratio of the additive to the substrate to be methylated is (0.5-2):1.

[0033] In some embodiments, the molar ratio of the methyl source to the substrate to be methylated is (2-12):1.

[0034] In some embodiments, the light source for the photocatalytic reaction includes blue light.

[0035] In some embodiments, the reaction temperature is 15°C to 30°C.

[0036] In some embodiments, the reaction time is 24 hours to 72 hours.

[0037] In a second aspect of the present invention, a class of α-methyl derivatives is provided, wherein the general structural formula of the α-methyl derivative is shown in formula (I):

[0038]

[0039] Dashed line, X, R 1 , R 2 , R 3 , R 4 The definition is the same as that of claim 1.

[0040] In some embodiments, the α-methyl derivative includes an α-methylamine derivative, and the α-methylamine derivative has the following general structural formula III:

[0041]

[0042] R 1Including phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl, 2,4-difluorophenyl, 4-trifluoromethylphenyl, 4-cyanophenyl, 4-phenylphenyl, 4-methoxyphenyl, 4-thiomethylphenyl, 4-N,N-dimethylphenyl, 4-tert-butylphenyl, 4-isopropylphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-methoxyphenyl, 3-trifluoromethylphenyl, 3-cyanophenyl phenyl, 2-hydroxyphenyl, 2-acetoxyphenyl, 2-methoxycarbonylphenyl, 2-fluorophenyl, 2-chlorophenyl, 2,2-difluoro[d][1,3]dihydroxybenzocyclopentyl, 2-naphthyl, 1-naphthyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-fluoro-2-pyridyl, 4-trifluoromethyl-2-pyridyl, 5-chloro-2-pyridyl, 3-N-methylindolyl, 2-thienyl, 3-thienyl or 2-quinolyl;

[0043] R 2 Including H, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 4-cyanophenyl, 4-nitrophenyl, 4-methoxyphenyl, 4-N,N-dimethylphenyl, 4-tert-butylphenyl, 3,4-difluorophenyl, 2-naphthyl, 2-pyridyl, 2-pyrimidyl, 2-quinolyl or 2-isoquinolyl;

[0044] R 3 Including acetyl, trifluoroacetyl, pivaloyl, cyclohexanoyl, tert-butyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, phenoxycarbonyl, benzenesulfonyl, benzoyl, 4-methoxybenzoyl, 4-tert-butylbenzoyl, 4-fluorobenzoyl, 4-cyanobenzoyl, 2,6-dichlorobenzoyl, 2-pyridoyl, phenylthiocarboyl or anilinoyl;

[0045] R 4 including H, D, methyl, methoxycarbonyl or phenyl;

[0046] Or the following α-methyl drug molecules and cyclic amine derivatives:

[0047]

[0048] In some embodiments, the α-methyl derivatives include α-methyl amino acids and dipeptide derivatives, and the general structural formula of the α-methyl amino acids and dipeptide derivatives is shown in the following formula (IV):

[0049]

[0050] R 1 and R 3 As claimed in claim 1;

[0051] R 1including methoxycarbonyl, L-valine carbonyl, L-alanine carbonyl, L-leucine carbonyl, L-isoleucine carbonyl or L-phenylalanine carbonyl;

[0052] R 3 These include acetyl or benzoyl.

[0053] In some embodiments, the α-methyl derivative includes an α-methyl ether / alcohol derivative, and the general structural formula of the α-methyl ether / alcohol derivative is shown in the following formula (VI):

[0054]

[0055] R 1 including phenyl, 4-cyanophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 3-methoxyphenyl, 4-tert-butylphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 4-trifluoromethylphenyl, benzo-2,2-difluoro[d][1,3]dihydroxycyclopentyl, 2-pyridyl, 4-chloro-2-pyridyl, 6-fluoro-2-pyridyl, 2-quinolyl, 2-naphthyl, 2-thienyl, 3-pyridyl, 4-pyridyl, ethynyl, phenylynyl, ethoxycarbonyl, methoxycarbonyl, isopropyloxycarbonyl or phenoxycarbonyl;

[0056] R 2 including H, phenyl, 4-fluorophenyl, 4-bromophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 4-cyanophenyl, 4-phenylphenyl, 4-tert-butylphenyl, 4-methoxycarbonylphenyl, 4-acetamidophenyl, 4-acetoxyphenyl, 2-iodophenyl, 2-methoxyphenyl, 3,5-dimethoxyphenyl, 1-naphthyl, 6-quinolyl, 3-methoxycarbonyl-2-naphthyl, methyl, isopropyl, 1-bromo-n-butyl, benzoyloxybutyl, acetyl, pivaloyl, benzoyl, 4-cyanobenzoyl or tert-butyloxycarbonyl;

[0057] R 4 Includes H, D, methoxycarbonyl, phenoxycarbonyl, tert-butyloxycarbonyl, phenylaminocarbonyl, tert-butylaminocarbonyl or methylaminocarbonyl.

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

[0059] In some embodiments, the eluent of the silica gel column chromatography method includes a mixed solvent of petroleum ether-ethyl acetate, a mixed solvent of petroleum ether-acetone, or a mixed solvent of dichloromethane-methanol.

[0060] The third aspect of the present invention provides the HFIP booster C(sp 3Application of the direct methylation synthesis method of )-H bonds 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 HFIP provided by the present invention helps C(sp 3 )-H bond direct methylation synthesis method, using light / nickel synergistic catalytic system, DTBP as methyl radical source, under mild conditions to achieve the N / O atom ortho C (sp 3 )-H methylation, with a high yield, and avoids the use of noble metals and methyl metal reagents, and also avoids strong bases and harsh reaction conditions. It is worth noting that this method is based on the principle of polarity matching and uses HFIP proton-type high-polarity solvent for the first time to form a stronger electrophilic hexafluoroisopropanol oxygen radical, thereby accelerating the reaction of C(sp 3 )-H hydrogen atom transfer process, thereby accelerating the generation of α-heteroatom alkyl radicals. The use of HFIP effectively solves the problem of low electron density C(sp 3 )-H in the free radical reaction, which prompted the C(sp 3 )-H bond direct methylation conversion.

[0063] The present invention provides easily prepared α-methylamines, α-methyl ethers, α-methyl alcohols and α-methyl polypeptide derivatives, laying a foundation for the later methylation derivatization application of complex drug molecules.

[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 following embodiments only illustrate the basic concept of the present invention in an illustrative 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 cannot be understood as indicating or implying relative importance or implicitly indicating the number of the indicated technical features. Therefore, the features defined as "first" and "second" may explicitly or implicitly include at least one of the features.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] Unless mentioned to the contrary, terms in the singular may include plural forms and should not be construed as being one in number.

[0073] 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.

[0074] 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.

[0075] 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).

[0076] 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.

[0077] 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.

[0078] 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 or 1 to 6. 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-hexyl, 1-methylhexyl, 2-ethylhexyl, 2-butylhexyl, cyclohexyl, adamantane, and the like.

[0079] 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 (-Ot-Bu).

[0080] "Aryl or aromatic group" refers to an aromatic hydrocarbon group derived from an aromatic ring compound by removing a hydrogen atom, which can 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 is optionally further substituted; suitable examples include, but are not limited to: benzene, biphenyl, terphenyl, naphthalene, anthracene, fluoranthene, phenanthrene, triphenylene, dinaphthylenediol, tetracene, pyrene, benzopyrene, acenaphthene, fluorene and their derivatives. 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), specifically acenaphthene, fluorene, or 9,9-diarylfluorene, triarylamine, diaryl ether systems should also be included in the definition of aromatic groups.

[0081] "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.

[0082] Based on the magical methylation effect, the present invention provides a HFIP-assisted C(sp 3 )-H bond direct methylation synthesis method. This method uses a light / nickel synergistic catalytic system and DTBP as a methyl radical source to achieve C(sp) synthesis of benzylamine / benzyl alcohol skeletons and various types of substrates in one step under mild conditions. 3 )H methylation, avoiding the use of noble metals and methyl metal reagents, and also avoiding strong bases and harsh reaction conditions. This method achieves C(sp) 3 )-H methylation. It is worth noting that this method is based on the principle of polarity matching and uses HFIP protic solvent for the first time to form a stronger electrophilic hexafluoroisopropanol oxygen radical, thereby accelerating the C(sp 3 )-H hydrogen atom transfer process, effectively solving the low electron density C(sp 3 )-H activity in free radical reactions.

[0083] In some examples, the α-methyl derivative I includes one of the structures shown below:

[0084]

[0085] In some of the examples, the photocatalytic reaction is followed by a separation step using silica gel column chromatography.

[0086] In some examples, the eluent of the silica gel column chromatography includes a petroleum ether-ethyl acetate mixed solvent, a petroleum ether-acetone mixed solvent or a dichloromethane-methanol mixed solvent.

[0087] Preferably, the volume ratio of the petroleum ether-ethyl acetate mixed solvent is (0.5-50):1; the volume ratio of the petroleum ether-acetone mixed solvent is (2-10):1; the volume ratio of the dichloromethane-methanol mixed solvent is (10-20):1.

[0088] Based on good functional group tolerance, the present invention can further realize direct methylation modification of complex drug molecules such as beclomethasone, flubutyric acid, itopride, etc.

[0089] In summary, the present invention provides a method for preparing C(sp 3 )-H direct methylation method, and has broad application prospects in the field of later derivatization and modification of natural products or candidate drugs.

[0090] 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.

[0091] 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.

[0092] Examples 1 to 29 provide different α-methyl derivatives and their preparation processes, as follows:

[0093] Example 1: Preparation of tert-butyl N-(1-phenylethyl)-N-(phenyl)carbamate I-1:

[0094] In a glove box, ethylene glycol dimethyl ether nickel chloride (10 mol%, 4.4 mg), 2,9-dimethyl-1,10-phenanthroline (12 mol%, 5.0 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) were added to a dry 1.5 mL transparent glass vial. Then, tert-butyl N-(benzyl)-N-(phenyl)carbamate (0.20 mmol, 56.7 mg), hexafluoroisopropanol (0.08 mL), tert-butyl peroxide (12.0 eq., 0.44 mL), and pyridine (1.0 eq., 0.016 mL) were added in sequence. The mixture was irradiated with 40 W blue light and 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 and eluted with petroleum ether / ethyl acetate (40:1) to obtain 41.8 mg of colorless oily liquid with a yield of 70%. A mixed solution of petroleum ether / ethyl acetate = 20 / 1 was used as the developing solvent. f =0.41, I-1 was prepared, and its chemical structure is as follows:

[0095]

[0096] 1 H NMR (400 MHz, CDCl 3 )δ7.29-7.17 (m, 8H), 6.81-6.80 (d, J=6.8Hz, 2H), 5.68-5.66 (m, 1H), 1.45 (d, J=7.2Hz, 3H), 1.35 (s, 9H). 13 C NMR (101 MHz, CDCl 3 )δ155.3, 142.5, 139.6, 129.9, 128.3, 128.2, 127.6, 127.3, 126.8, 80.2, 55.2, 28.5, 18.2.HRMS (ESI): C 19 H 24 NO 2 [M+H] + The calculated exact molecular weight is 298.1802, and the measured value is 298.1804.

[0097] Example 2: Preparation of tert-butyl N-(1-(3,4-difluorophenyl)ethyl)-N-(phenyl)carbamate I-2:

[0098] In a glove box, ethylene glycol dimethyl ether nickel chloride (10 mol%, 4.4 mg), 2,9-dimethyl-1,10-phenanthroline (12 mol%, 5.0 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) were added to a dry 1.5 mL transparent glass vial, and then tert-butyl N-(3,4-difluorophenylmethyl)-N-(phenyl)carbamate (0.20 mmol, 63.8 mg), hexafluoroisopropanol (0.08 mL), tert-butyl peroxide (12.0 eq., 0.44 mL), and pyridine (1.0 eq., 0.016 mL) were added in sequence. The mixture was irradiated with 40 W blue light and 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 and eluted with petroleum ether / ethyl acetate (40:1) to obtain 46.5 mg of colorless oily liquid with a yield of 70%. A mixed solution of petroleum ether / ethyl acetate = 20 / 1 was used as the developing solvent. f =0.48, I-2 was prepared, and its chemical structure is as follows:

[0099]

[0100] 1 H NMR (400 MHz, CDCl 3 )δ7.26-7.21(m, 3H), 7.10-7.04(m, 2H), 7.02-6.99(m, 1H), 6.81-6.79(m, 2H), 5.64-5.62(m, 1H), 1.42(d, J=6.8Hz, 3H), 1.36(s, 9H). 13 C NMR (101 MHz, CDCl 3 )δ155.1, 150.2 (dd, J=248.7, 12.6Hz), 149.6 (dd, J=248.8, 12.7Hz), 139.7 (t, J=4.3Hz), 139.2, 129.7, 1 28.6, 127.1, 123.6 (dd, J=6.2, 3.5Hz), 116.9 (d, J=17.2Hz), 116.6 (d, J=17.5Hz), 80.5, 54.2, 28.4, 18.3. 19 F NMR (377 MHz, CDCl 3 )δ-138.0(m),-140.1(m).HRMS(ESI): C 19 H 22 F 2 NO 2 [M+H]+ The calculated exact molecular weight is 334.1613, and the measured value is 334.1614.

[0101] Example 3: Preparation of tert-butyl N-(1-(4-trifluoromethylphenyl)ethyl)-N-(phenyl)carbamate I-3

[0102] In a glove box, ethylene glycol dimethyl ether nickel chloride (10 mol%, 4.4 mg), 2,9-dimethyl-1,10-phenanthroline (12 mol%, 5.0 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) were added to a dry 1.5 mL transparent glass vial, and then tert-butyl N-(4-trifluoromethylphenylmethyl)-N-(phenyl)carbamate (0.20 mmol, 70.2 mg), hexafluoroisopropanol (0.08 mL), tert-butyl peroxide (12.0 eq., 0.44 mL), and pyridine (1.0 eq., 0.016 mL) were added in sequence. The mixture was irradiated with 40 W blue light and 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 / ethyl acetate (40:1), and 45.1 mg of colorless oily liquid was obtained with a yield of 62%. A mixed solution of petroleum ether / ethyl acetate = 20 / 1 was used as the developing solvent. f =0.43, I-3 was prepared, and its chemical structure is as follows:

[0103]

[0104] 1 H NMR (400 MHz, CDCl 3 )δ7.56 (d, J=8.4Hz, 2H), 7.40 (d, J=8.4Hz, 2H), 7.27-7.21 (m, 3H), 6.84 (d, J=6.8Hz, 2H), 5.69-5.67 (m, 1H), 1.48 (d, J=7.2Hz, 3H), 1.35 (s, 9H). 13 CNMR (101MHz, CDCl 3 ) δ155.2, 146.7, 139.4, 129.7, 129.5 (q, J=32.2Hz), 128.6, 127.8, 127.1, 125.2 (q, J=3.8Hz), 124.4 (q, J=273.0Hz), 80.5, 55.0, 28.4, 18.3. 19 F NMR (377 MHz, CDCl 3)δ-62.4.HRMS(ESI):C 20 H 22 F 3 NNaO 2 [M+Na] + The calculated precise molecular weight is 388.1495 and the measured value is 388.1498.

[0105] Example 4: Preparation of tert-butyl N-(1-(naphthalen-2-yl)ethyl)-N-(phenyl)carbamate I-4

[0106] In a glove box, ethylene glycol dimethyl ether nickel chloride (10 mol%, 4.4 mg), 2,9-dimethyl-1,10-phenanthroline (12 mol%, 5.0 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), and then N-(1-(naphthalene-2-yl)methyl)-N-(phenyl)carbamic acid tert-butyl ester (0.20 mmol, 66.6 mg), hexafluoroisopropanol (0.1 mL), tert-butyl peroxide (12.0 eq., 0.44 mL), pyridine (1.0 eq., 0.016 mL) were added in sequence, 40 W 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 and eluted with petroleum ether / ethyl acetate (50:1) to obtain 43.6 mg of colorless oily liquid with a yield of 63%. A mixed solution of petroleum ether / ethyl acetate = 30 / 1 was used as the developing solvent. R f =0.48, I-4 was prepared, and its chemical structure is as follows:

[0107]

[0108] 1 H NMR (400 MHz, CDCl 3 )δ7.84-7.75(m, 3H), 7.62(s, 1H), 7.51(dd, J=8.8, 1.6Hz, 1H), 7.49-7.44(m, 2H), 7.19 -7.17(m, 3H), 6.87-6.77(m, 2H), 5.88-5.87(m, 1H), 1.57(d, J=7.2Hz, 3H), 1.39(s, 9H). 13 C NMR (101 MHz, CDCl 3)6155.4, 140.0, 139.5, 133.3, 132.8, 129.9, 128.4, 128.2, 127.9, 127.7, 126.9, 126.4, 126.1, 125.91, 125.85, 80.3, 55.1, 28.5, 18.2.HRMS (ESI): C 23 H 25 NNaO 2 [M+Na] + The calculated exact molecular weight is 370.1778 and the measured value is 370.1777.

[0109] Example 5: Preparation of tert-butyl N-(1-(6-fluoropyridin-2-yl)ethyl)-N-(phenyl)carbamate I-5

[0110] In a glove box, ethylene glycol dimethyl ether nickel chloride (10 mol%, 4.4 mg), 2,9-dimethyl-1,10-phenanthroline (12 mol%, 5.0 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%) were added to a dry 1.5 mL clear glass vial. %, 2.2mg), and then N-(1-(6-fluoropyridin-2-yl)methyl)-N-(phenyl)carbamic acid tert-butyl ester (0.20mmol, 60.4mg), hexafluoroisopropanol (0.08mL), tert-butyl peroxide (12.0eq., 0.44mL), pyridine (1.0eq., 0.016mL) 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 and eluted with petroleum ether / ethyl acetate (15:1) to obtain 40.2mg colorless oily liquid with a yield of 64%. A mixed solution of petroleum ether / ethyl acetate = 7 / 1 was used as the developing solvent. R f =0.50, I-5 was prepared, and its chemical structure is as follows:

[0111]

[0112] 1 H NMR (400 MHz, CDCl 3 )δ7.75(q, J=8.0Hz, 1H), 7.33-7.26(m, 3H), 7.23-7.20(m, 1H), 7.14-7.12(m, 2H), 6. 79 (dd, J=8.0, 3.2Hz, 1H), 5.40 (q, J=7.2Hz, 1H), 1.48 (d, J=7.2Hz, 3H), 1.33 (s, 9H). 13C NMR (101 MHz, CDCl 3 ) δ 163.1 (d, J = 239.4Hz), 161.5 (d, J = 12.7Hz), 155.0, 141.2 (d, J = 7.5Hz), 140.5, 12 9.3, 128.6, 126.9, 119.0 (d, J=4.1Hz), 107.5 (d, J=37.7Hz), 80.5, 57.7, 28.4, 17.9. 19 F NMR (377 MHz, CDCl 3 )δ-67.4.HRMS(ESI):C 18 H 22 FN 2 O 2 [M+H] + The calculated exact molecular weight is 317.1660, and the measured value is 317.1662.

[0113] Example 6: Preparation of tert-butyl N-(1-phenylethyl)-N-(pyridin-2-yl)carbamate I-6:

[0114] In a glove box, ethylene glycol dimethyl ether nickel chloride (10 mol%, 4.4 mg), 2,9-dimethyl-1,10-phenanthroline (12 mol%, 5.0 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) were added to a dry 1.5 mL transparent glass vial, and then tert-butyl N-(benzyl)-N-(pyridin-2-yl)carbamate (0.20 mmol, 56.8 mg), hexafluoroisopropanol (0.08 mL), tert-butyl peroxide (12.0 eq., 0.44 mL), and pyridine (1.0 eq., 0.016 mL) were added in sequence. The mixture was irradiated with 40 W blue light and 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 and eluted with petroleum ether / ethyl acetate (15:1) to obtain 32.3 mg of colorless oily liquid with a yield of 54%. A mixed solution of petroleum ether / ethyl acetate = 5 / 1 was used as the developing solvent. f =0.67, I-6 was prepared, and its chemical structure is as follows:

[0115]

[0116] 1 H NMR (400 MHz, CDCl 3)δ8.45-8.43(m, 1H), 7.62-7.57(m, 1H), 7.41-7.39(m, 2H), 7.30-7.24(m, 3H), 7.22-7. 18 (m, 1H), 7.08-7.05 (m, 1H), 5.77 (q, J=6.9Hz, 1H), 1.70 (d, J=7.2Hz, 3H), 1.27 (s, 9H). 13 C NMR (101 MHz, CDCl 3 )δ154.8, 154.5, 148.2, 143.3, 137.0, 128.1, 127.0, 126.7, 122.5, 120.7, 80.9, 55.8, 28.3, 18.5.HRMS (ESI): C 18 H 23 N 2 O 2 [M+H] + The calculated exact molecular weight is 299.1754, and the measured value is 299.1751.

[0117] Example 7: Preparation of N-(1-(4-bromophenyl)ethyl)benzamide I-7

[0118] In a glove box, tetrapyridine nickel chloride (5 mol%, 4.5 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%, 2.2 mg) were added to a dry 1.5 mL transparent glass vial, and then N-(1-(4-bromophenyl)methyl)benzamide (0.20 mmol, 58.0 mg), hexafluoroisopropanol (0.12 mL), and tert-butyl peroxide (5.0 eq., 0.18 mL) were added in sequence. The mixture was irradiated with 40 W blue light and reacted at room temperature for 36 hours. The reaction was monitored by TLC. After the reaction, the crude product was purified by silica gel column chromatography and eluted with petroleum ether / ethyl acetate (10:1) to obtain 34.2 mg of white solid with a yield of 56%. A mixed solution of petroleum ether / ethyl acetate = 5 / 1 was used as the developing solvent. f =0.39, I-7 was prepared, and its chemical structure is as follows:

[0119]

[0120] 1 H NMR (400 MHz, CDCl 3)δ7.77-7.75 (m, 2H), 7.52-7.40 (m, 5H), 7.27-7.25 (m, 2H), 6.35 (d, J = 5.6Hz, 1H), 5.28 (p, J = 7.2Hz, 1H), 1.57 (d, J = 6.8Hz, 3H). 13 C NMR (101 MHz, CDCl 3 )δ166.8, 142.4, 134.5, 131.9, 131.8, 128.8, 128.1, 127.1, 121.4, 48.9, 21.8.HRMS (ESI): C 15 H 15 BrNO[M+H] + The calculated exact molecular weight is 304.0332, and the measured value is 304.0330.

[0121] Example 8: Preparation of N-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethyl)benzamide I-8

[0122] In a glove box, tetrapyridine nickel chloride (5 mol%, 4.5 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) were added to a dry 1.5 mL transparent glass vial, and then N-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)methyl)benzamide (0.20 mmol, 58.2 mg), hexafluoroisopropanol (0.20 mL), and tert-butyl peroxide (6.0 eq., 0.22 mL) were added in sequence. The mixture was irradiated with 40 W blue light and reacted at room temperature for 45 hours. The reaction was monitored by TLC. After the reaction, the crude product was purified by silica gel column chromatography and eluted with petroleum ether / ethyl acetate (15:1) to obtain 37.8 mg of white solid with a yield of 62%. A mixed solution of petroleum ether / ethyl acetate = 5 / 1 was used as the developing solvent. f =0.61, I-8 was prepared, and its chemical structure is as follows:

[0123]

[0124] 1 H NMR (400 MHz, CDCl 3)δ7.77-7.75(m, 2H), 7.53-7.48(m, 1H), 7.44-7.40(m, 2H), 7.11-7.09(m, 2H), 7.0 1-6.99 (m, 1H), 6.40 (d, J=6.8Hz, 1H), 5.28 (p, J=7.2Hz, 1H), 1.58 (d, J=6.8Hz, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ166.8, 144.2, 143.1, 140.0, 134.4, 131.8, 129.3 (t, J=217.0Hz), 128.8, 127.1, 121.5, 109.6, 107.8, 49.2, 22.2. 19 F NMR (377 MHz, CDCl 3 )δ-50.0.HRMS(ESI):C 16 H 13 F 2 NNaO 3 [M+Na] + The calculated exact molecular weight is 328.0756, and the measured value is 328.0756.

[0125] Example 9: Preparation of 2-(1-benzamidoethyl)phenyl acetate I-9

[0126] In a glove box, tetrapyridine nickel chloride (5 mol%, 4.5 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%, 2.2 mg) were added to a dry 1.5 mL transparent glass vial, and then 2-(1-benzamidomethyl)phenyl acetate (0.20 mmol, 53.8 mg), hexafluoroisopropanol (0.16 mL), tert-butyl peroxide (6.0 eq., 0.22 mL) were added in sequence, 40 W blue light was irradiated, and the reaction was reacted at room temperature for 36 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 43.8 mg of white solid was obtained, with a yield of 77%. A mixed solution of petroleum ether / ethyl acetate = 5 / 1 was used as the developing solvent, R f =0.33, I-9 was prepared, and its chemical structure is as follows:

[0127]

[0128] 1 H NMR (400 MHz, CDCl 3)δ7.73-7.71(m, 2H), 7.49-7.45(m, 2H), 7.42-7.38(m, 2H), 7.36-7.32(m, 1H), 7.29-7.25(m, 1H), 7 .10-7.08 (m, 1H), 6.29 (d, J=7.2Hz, 1H), 5.52 (p, J=7.2Hz, 1H), 2.29 (s, 3H), 1.59 (d, J=7.2Hz, 3H). 13 C NMR (101 MHz, CDCl 3 )δ170.1, 166.5, 148.9, 134.6, 134.4, 131.6, 128.9, 128.7, 127.2, 127.0, 126.6, 123.4, 44.4, 21.1, 20.4.HRMS (ESI): C 17 H 18 NO 3 [M+H] + The calculated exact molecular weight is 284.1281 and the measured value is 284.1279.

[0129] Example 10: Preparation of N-(1-(pyridin-2-yl)ethyl)benzenesulfonamide I-10:

[0130] In a glove box, tetrapyridine nickel chloride (5 mol%, 4.5 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%, 2.2 mg) were added to a dry 1.5 mL transparent glass vial, and then N-(1-(pyridin-2-yl)methyl)benzenesulfonamide (0.20 mmol, 49.6 mg), hexafluoroisopropanol (0.16 mL), and tert-butyl peroxide (6.0 eq., 0.22 mL) were added in sequence. The mixture was irradiated with 40 W blue light and 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 and eluted with petroleum ether / ethyl acetate (2:1) to obtain 28.3 mg of a white solid with a yield of 54%. A mixed solution of petroleum ether / ethyl acetate = 1:1 was used as the developing solvent. f =0.35, I-10 was prepared, and its chemical structure is as follows:

[0131]

[0132] 1 H NMR (400 MHz, CDCl 3)δ8.38 (d, J=4.0Hz, 1H), 7.73 (d, J=8.0Hz, 2H), 7.52-7.48 (m, 1H), 7.43-7.39 (m, 1H), 7.34-7.30 (m, 2H), 7. 09-7.06 (m, 1H), 6.99 (d, J=8.0Hz, 1H), 6.19 (d, J=7.2Hz, 1H), 4.51 (p, J=7.2Hz, 1H), 1.45 (d, J=6.8Hz, 3H). 13 C NMR (101 MHz, CDCl 3 )δ159.7, 149.0, 140.7, 136.8, 132.3, 128.8, 127.2, 122.5, 121.1, 53.8, 24.0.HRMS (ESI): C 13 H 15 N 2 O 2 S[M+H] + The calculated exact molecular weight is 263.0849 and the measured value is 263.0847.

[0133] Example 11: Preparation of N-(1-(thiophen-2-yl)ethyl)benzamide I-11:

[0134] In a glove box, tetrapyridine nickel chloride (5 mol%, 4.5 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%, 2.2 mg) were added to a dry 1.5 mL transparent glass vial, and then N-(1-(thiophen-2-yl)methyl)benzamide (0.20 mmol, 43.4 mg), hexafluoroisopropanol (0.16 mL), and tert-butyl peroxide (6.0 eq., 0.22 mL) were added in sequence. The mixture was irradiated with 40 W blue light and 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 and eluted with petroleum ether / ethyl acetate (10:1) to obtain 20.3 mg of a white solid with a yield of 44%. A mixed solution of petroleum ether / ethyl acetate = 5 / 1 was used as the developing solvent. f =0.46, I-11 was prepared, and its chemical structure is as follows:

[0135]

[0136] 1 H NMR (400 MHz, CDCl 3)δ7.78-7.76(m, 2H), 7.52-7.48(m, 1H), 7.44-7.41(m, 2H), 7.24-7.22(m, 1H), 7.05-7.04(m , 1H), 6.99-6.97 (m, 1H), 6.36 (d, J=5.6Hz, 1H), 5.62 (p, J=7.2Hz, 1H), 1.70 (d, J=6.8Hz, 3H). 13 C NMR (101 MHz, CDCl 3 )δ166.5, 147.2, 134.6, 131.7, 128.7, 127.11, 127.06, 124.6, 124.3, 45.2, 22.3.HRMS (ESI): C 13 H 13 NNaOS[M+Na] + The calculated exact molecular weight is 254.0610, and the measured value is 254.0612.

[0137] Example 12: Preparation of benzoylalanine methyl ester I-12

[0138] In a glove box, tetrapyridine nickel chloride (5 mol%, 4.5 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) were added to a dry 1.5 mL transparent glass vial, and then benzoylglycine methyl ester (0.20 mmol, 38.6 mg), hexafluoroisopropanol (0.16 mL), tert-butyl peroxide (6.0 eq., 0.22 mL) were added in sequence, 40 W blue light was irradiated, and the reaction was reacted at room temperature for 36 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 (5:1), and 26.5 mg of colorless oily liquid 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 =0.56, I-12 was prepared, and its chemical structure is as follows:

[0139]

[0140] 1 H NMR (400 MHz, CDCl 3 )δ7.81-7.79 (m, 2H), 7.52-7.41 (m, 3H), 6.77 (br, 1H), 4.80 (p, J=7.2Hz, 1H), 3.78 (s, 3H), 1.52 (d, J=6.8Hz, 3H). 13C NMR (101 MHz, CDCl 3 )δ173.8, 166.9, 134.1, 131.8, 128.7, 127.2, 52.7, 48.6, 18.8.HRMS (ESI): C 11 H 13 NNaO 3 [M+Na] + The calculated exact molecular weight is 230.0788 and the measured value is 230.0788.

[0141] Example 13: Preparation of 2-acetyl-3-methylisoindol-1-one I-13

[0142] In a glove box, tetrapyridine nickel chloride (5 mol%, 4.5 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%, 2.2 mg) were added to a dry 1.5 mL transparent glass vial, and then 2-acetylisoindol-1-one (0.20 mmol, 35.0 mg), hexafluoroisopropanol (0.20 mL), tert-butyl peroxide (4.0 eq., 0.147 mL) were added in sequence, 40 W blue light was irradiated, and the reaction was reacted at room temperature for 36 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 20.3 mg of white solid was obtained, with a yield of 54%. A mixed solution of petroleum ether / ethyl acetate = 5 / 1 was used as the developing solvent, R f =0.54, I-13 was prepared, and its chemical structure is as follows:

[0143]

[0144] 1 H NMR (400 MHz, CDCl 3 )δ7.89 (d, J=7.6Hz, 1H), 7.67 (td, J=7.6, 1.2Hz, 1H), 7.52-7.45 (m, 2H), 5.21 (q, J=6.4Hz, 1H), 2.67 (s, 3H), 1.61 (d, J=6.4Hz, 3H). 13 C NMR (101 MHz, CDCl 3 )δ171.3, 168.0, 147.8, 134.4, 130.1, 128.8, 125.3, 122.7, 55.8, 25.7, 20.3.HRMS (ESI): C 11 H 12 NO 2[M+H] + The calculated precise molecular weight is 190.0863 and the measured value is 190.0864.

[0145] Example 14: Preparation of (2-methylpyrrolidin-1-yl)(phenyl)methanone I-14

[0146] In a glove box, tetrapyridine nickel chloride (5 mol%, 4.5 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%, 2.2 mg) were added to a dry 1.5 mL transparent glass vial, and then (pyrrolidin-1-yl)(phenyl)methanone (0.20 mmol, 35.0 mg), hexafluoroisopropanol (0.24 mL), and tert-butyl peroxide (4.0 eq., 0.147 mL) were added in sequence. The mixture was irradiated with 40 W blue light and 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 / ethyl acetate (5:1), and 18.2 mg of colorless oily liquid was obtained with a yield of 48%. A mixed solution of petroleum ether / ethyl acetate = 3 / 1 was used as the developing solvent. f =0.45, I-14 was prepared, and its chemical structure is as follows:

[0147]

[0148] 1 H NMR (400 MHz, CDCl 3 )δ7.49-7.35(m, 5H), 4.36-4.31(m, 0.7H), 4.05-3.93(m, 0.3H), 3.72-3.65(m, 0.6H), 3.50-3.38(m, 1.4H), 2.19-2.11( m, 0.7H), 1.93-1.87 (m, 1.4H), 1.77-1.72 (m, 0.7H), 1.64-1.56 (m, 1.4H), 1.36 (d, J=6.0Hz, 2.1H), 0.96-0.85 (m, 0.9H). 13 C NMR (101 MHz, CDCl 3 )6169.9, 137.8, 129.9, 128.3, 127.3, 53.4, 50.1, 33.0, 25.1, 20.1.HRMS (ESI): C 12 H 16 NO[M+H] + The calculated exact molecular weight is 190.1226 and the measured value is 190.1227.

[0149] Example 15: Preparation of N-(2-phenylpropan-2-yl)benzamide I-15

[0150] In a glove box, tetrapyridine nickel chloride (5 mol%, 4.5 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%, 2.2 mg) were added to a dry 1.5 mL transparent glass vial, and then N-(1-phenylethyl)benzamide (0.20 mmol, 45.0 mg), hexafluoroisopropanol (0.16 mL), tert-butyl peroxide (6.0 eq., 0.22 mL) were added in sequence, 40 W blue light was irradiated, and the reaction was reacted at room temperature for 45 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 24.3 mg of white solid was obtained, with a yield of 51%. A mixed solution of petroleum ether / ethyl acetate = 5 / 1 was used as the developing solvent, R f =0.39, I-15 was prepared, and its chemical structure is as follows:

[0151]

[0152] 1 H NMR (400 MHz, CDCl 3 )δ7.77-7.75(m, 2H), 7.51-7.41(m, 5H), 7.37-7.33(m, 2H), 7.27-7.23(m, 1H), 6.41(bs, 1H), 1.83(s, 6H). 13 C NMR (101 MHz, CDCl 3 )δ166.6, 147.0, 135.6, 131.5, 128.69, 128.66, 127.0, 126.9, 124.9, 56.5, 29.3.HRMS (ESI): C 16 H 17 NNaO[M+Na] + The calculated exact molecular weight is 262.1202, and the measured value is 262.1204.

[0153] Example 16: Preparation of 6-(1-(pyridin-2-yl)ethoxy)quinoline I-16

[0154] In a glove box, ethylene glycol dimethyl ether nickel chloride (10 mol%, 4.4 mg), 2,9-dimethyl-1,10-phenanthroline (12 mol%, 5.0 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) were added to a dry 1.5 mL transparent glass vial, and then 6-(1-(pyridin-2-yl)methoxy)quinoline (0.20 mmol, 47.2 mg), hexafluoroisopropanol (0.15 mL), tert-butyl peroxide (12.0 eq., 0.44 mL), and pyridine (1.0 eq., 0.016 mL) were added in sequence. The mixture was irradiated with 40 W blue light and 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 / ethyl acetate (2:1), and 31.5 mg of light yellow oily liquid was obtained. The yield was 63%. A mixed solution of petroleum ether / ethyl acetate = 1 / 1 was used as the developing solvent. f =0.24, I-16 was prepared, and its chemical structure is as follows:

[0155]

[0156] 1 H NMR (400 MHz, CDCl 3 )δ8.73-8.72 (m, 1H), 8.62-8.60 (m, 1H), 7.98 (d, J=9.2Hz, 1H), 7.92-7.89 (m, 1H), 7.64 (td, J=7.6, 1.6Hz, 1H), 7.46-7 .43 (m, 2H), 7.29-7.26 (m, 1H), 7.20-7.17 (m, 1H), 6.97 (d, J = 2.8Hz, 1H), 5.56 (q, J = 6.4Hz, 1H), 1.75 (d, J = 6.4Hz, 3H).

[0157] 13 C NMR (101 MHz, acetone-d 6 )δ162.9, 156.8, 150.1, 149.0, 145.5, 138.0, 135.6, 132.0, 130.2, 123.6, 123.5, 122.4, 120.6, 109.2, 78.1, 22.7.HRMS (ESI): C 16 H 14 N 2 NaO[M+Na] + The calculated exact molecular weight is 273.0998 and the measured value is 273.0997.

[0158] Example 17: Preparation of 2-(1-(2-iodophenoxy)ethyl)pyridine I-17

[0159] In a glove box, ethylene glycol dimethyl ether nickel chloride (10 mol%, 4.4 mg), 2,9-dimethyl-1,10-phenanthroline (12 mol%, 5.0 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) were added to a dry 1.5 mL transparent glass vial, and then 2-(1-(2-iodophenoxy)methyl)pyridine (0.20 mmol, 62.2 mg), hexafluoroisopropanol (0.15 mL), tert-butyl peroxide (6.0 eq., 0.22 mL), pyridine (1.0 eq., 0.016 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 and eluted with petroleum ether / ethyl acetate (15:1) to obtain 53.2 mg of colorless oily liquid with a yield of 82%. A mixed solution of petroleum ether / ethyl acetate = 8 / 1 was used as the developing solvent. f =0.33, I-17 was prepared, and its chemical structure is as follows:

[0160]

[0161] 1 H NMR (400 MHz, CDCl 3 )δ8.56 (d, J=4.4Hz, 1H), 7.77 (dd, J=8.0, 1.6Hz, 1H), 7.68 (td, J=7.6, 1.6Hz, 1H), 7.54-7.5 2(m, 1H), 7.20-7.12(m, 2H), 6.70-6.63(m, 2H), 5.48(q, J=6.4Hz, 1H), 1.74(d, J=6.4Hz, 3H). 13 C NMR (101MHz, CDCb) δ162.1, 156.4, 149.0, 139.7, 137.3, 129.4, 122.8, 122.7, 120.1, 113.9, 87.3, 78.4, 22.7.HRMS (ESI): C 13 H 12 INNaO[M+Na] + The calculated exact molecular weight is 347.9856 and the measured value is 347.9853.

[0162] Example 18: Preparation of methyl 3-(1-(pyridin-2-yl)ethoxy)-2-naphthoate I-18

[0163] In a glove box, ethylene glycol dimethyl ether nickel chloride (10 mol%, 4.4 mg), 2,9-dimethyl-1,10-phenanthroline (12 mol%, 5.0 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) were added to a dry 1.5 mL transparent glass vial, and then 3-(1-(pyridin-2-yl)methoxy)-2-naphthoic acid methyl ester (0.20 mmol, 58.6 mg), hexafluoroisopropanol (0.15 mL), tert-butyl peroxide (12.0 eq., 0.44 mL), pyridine (1.0 eq., 0.016 mL), 40 W blue light irradiation, reaction at room temperature for 48 hours, TLC monitoring the reaction. After the reaction, the crude product was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (12:1), and 37.6 mg of colorless oily liquid was obtained, with a yield of 61%. A mixed solution of petroleum ether / ethyl acetate = 4 / 1 was used as the developing solvent, R f =0.25, I-18 was prepared, and its chemical structure is as follows:

[0164]

[0165] 1 H NMR (400 MHz, CDCl 3 )δ8.60-8.58(m, 1H), 8.27(s, 1H), 7.77(d, J=8.0Hz, 1H), 7.67-7.62(m, 2H), 7.58(d, J=8.4Hz, 1H), 7.45-7.41(m, 1H), 7.34-7.30 (m, 1H), 7.20-7.14 (m, 1H), 7.09 (s, 1H), 5.64 (q, J=6.4Hz, 1H), 4.00 (s, 3H), 1.76 (d, J=6.4Hz, 3H). 13 C NMR (101 MHz, CDCl 3 )δ167.0, 162.5, 153.6, 149.0, 137.3, 136.0, 132.7, 128.6, 128.3, 127.7, 126.7, 124.6, 122.7, 122.6, 120.1, 109.9, 77.8, 52.3, 22.6.HRMS (ESI): C 19 H 18 NO 3 [M+H]+ The calculated exact molecular weight is 308.1281 and the measured value is 308.1277.

[0166] Example 19: Preparation of 2-(1-methoxyethyl)quinoline I-19

[0167] In a glove box, ethylene glycol dimethyl ether nickel chloride (10 mol%, 4.4 mg), 2,9-dimethyl-1,10-phenanthroline (12 mol%, 5.0 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) were added to a dry 1.5 mL transparent glass vial, and then 2-(1-methoxymethyl)quinoline (0.20 mmol, 34.6 mg), hexafluoroisopropanol (0.15 mL), tert-butyl peroxide (6.0 eq., 0.22 mL), and pyridine (1.0 eq., 0.016 mL) were added in sequence. The mixture was irradiated with 40 W blue light and 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 and eluted with petroleum ether / ethyl acetate (15:1) to obtain 22.0 mg of colorless oily liquid with a yield of 59%. A mixed solution of petroleum ether / ethyl acetate = 8 / 1 was used as the developing solvent. f =0.32, I-19 was prepared, and its chemical structure is as follows:

[0168]

[0169] 1 H NMR (400 MHz, CDCl 3 )δ8.19 (d, J=8.4Hz, 1H), 8.08 (d, J=8.4Hz, 1H), 7.83-7.81 (m, 1H), 7.73-7.69 (m, 1H), 7.58 (d , J=8.4Hz, 1H), 7.55-7.51 (m, 1H), 4.62 (q, J=6.4Hz, 1H), 3.33 (s, 3H), 1.54 (d, J=6.4Hz, 3H). 13 C NMR (101 MHz, CDCl 3 )δ163.9, 147.6, 137.2, 129.6, 129.2, 127.8, 127.7, 126.4, 117.9, 81.6, 57.2, 22.5.HRMS (ESI): C 12 H 13 NNaO[M+Na] + The calculated exact molecular weight is 210.0889, and the measured value is 210.0889.

[0170] Example 20: Preparation of 2-(1-(4-bromobutoxy)ethyl)quinoline I-20

[0171] In a glove box, ethylene glycol dimethyl ether nickel chloride (10 mol%, 4.4 mg), 2,9-dimethyl-1,10-phenanthroline (12 mol%, 5.0 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) were added to a dry 1.5 mL transparent glass vial, and then 2-(1-(4-bromobutoxy)ethyl)quinoline (0.20 mmol, 58.8 mg), hexafluoroisopropanol (0.15 mL), tert-butyl peroxide (8.0 eq., 0.294 mL), and pyridine (1.0 eq., 0.016 mL) were added in sequence. The mixture was irradiated with 40 W blue light and 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 and eluted with petroleum ether / ethyl acetate (30:1) to obtain 22.1 mg of colorless oily liquid with a yield of 36%. A mixed solution of petroleum ether / ethyl acetate = 8 / 1 was used as the developing solvent. f =0.31, I-20 was prepared, and its chemical structure is as follows:

[0172]

[0173] 1 H NMR (400 MHz, CDCl 3 )δ8.19 (d, J=8.4Hz, 1H), 8.07 (d, J=8.4Hz, 1H), 7.82 (d, J=8.0Hz, 1H), 7.73-7.69 (m, 1H), 7.58 (d, J=8.8Hz, 1H), 7.55-7.51 (m, 1H), 4.70 ( q, J=6.8Hz, 1H), 3.52-3.46 (m, 1H), 3.42 (t, J=6.8Hz, 2H), 3.39-3.33 (m, 1H), 1.99-1.92 (m, 2H), 1.78-1.70 (m, 2H), 1.54 (d, J=6.8Hz, 3H). 13 C NMR (101 MHz, CDCl 3 )δ164.3, 147.5, 137.3, 129.7, 129.2, 127.78, 127.76, 126.4, 117.9, 80.1, 68.4, 33.7, 29.9, 28.8, 22.6.HRMS (ESI): C 15 H 18BrNNaO[M+Na] + The calculated exact molecular weight is 330.0464 and the measured value is 330.0463.

[0174] Example 21: Preparation of ethyl 2-phenoxypropionate I-21

[0175] In a glove box, ethylene glycol dimethyl ether nickel chloride (10 mol%, 4.4 mg), 2,9-dimethyl-1,10-phenanthroline (12 mol%, 5.0 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) were added to a dry 1.5 mL transparent glass vial, and then ethyl 2-phenoxyacetate (0.20 mmol, 36.0 mg), hexafluoroisopropanol (0.15 mL), tert-butyl peroxide (8.0 eq., 0.294 mL), and pyridine (1.0 eq., 0.016 mL) were added in sequence. The mixture was irradiated with 40 W blue light and 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 and eluted with petroleum ether / ethyl acetate (80:1) to obtain 23.3 mg of colorless oily liquid with a yield of 60%. A mixed solution of petroleum ether / ethyl acetate = 15 / 1 was used as the developing solvent. f =0.45, I-21 was prepared, and its chemical structure is as follows:

[0176]

[0177] 1 H NMR (400 MHz, CDCl 3 )δ7.30-7.24(m, 2H), 6.99-6.95(m, 1H), 6.89-6.86(m, 2H), 4.74(q, J=6.8H z, 1H), 4.22 (q, J=6.8Hz, 2H), 1.62 (d, J=6.8Hz, 3H), 1.25 (t, J=7.2Hz, 3H).

[0178] 13 C NMR (101 MHz, CDCl 3 )δ172.4, 157.8, 129.6, 121.7, 115.3, 72.8, 61.4, 18.7, 14.3.HRMS (ESI): C 11 H 14 NaO 3 [M+Na] + The calculated exact molecular weight is 217.0835, and the measured value is 217.0833.

[0179] Example 22: Preparation of 4-(but-3-yn-2-oxy)benzonitrile 1-22

[0180] In a glove box, ethylene glycol dimethyl ether nickel chloride (10 mol%, 4.4 mg), 2,9-dimethyl-1,10-phenanthroline (12 mol%, 5.0 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) were added to a dry 1.5 mL transparent glass vial, and then 4-(prop-2-yn-2-oxy)benzonitrile (0.20 mmol, 31.4 mg), hexafluoroisopropanol (0.15 mL), tert-butyl peroxide (12.0 eq., 0.44 mL), and pyridine (1.0 eq., 0.016 mL) were added in sequence. The mixture was irradiated with 40 W blue light and 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 and eluted with petroleum ether / ethyl acetate (70:1) to obtain 6.8 mg of colorless oily liquid with a yield of 20%. A mixed solution of petroleum ether / ethyl acetate = 15 / 1 was used as the developing solvent. f =0.32, I-22 was prepared, and its chemical structure is as follows:

[0181]

[0182] 1 H NMR (400 MHz, CDCl 3 )δ7.62-7.58 (m, 2H), 7.08-7.04 (m, 2H), 4.90 (qd, J=6.4Hz, J=2.0Hz, 1H), 2.52 (d, J=2.0Hz, 1H), 1.70 (J=6.4Hz, 3H). 13 C NMR (101 MHz, CDCl 3 )δ159.7, 133.0, 118.2, 115.4, 103.9, 80.8, 74.0, 63.0, 21.1.HRMS (ESI): C 11 H 9 NNaO[M+Na] + The calculated exact molecular weight is 194.0576 and the measured value is 194.0579.

[0183] Example 23: Preparation of 4-(1-phenylethoxy)phenyl acetate I-23

[0184] In a glove box, ethylene glycol dimethyl ether nickel chloride (10 mol%, 4.4 mg), 2,9-dimethyl-1,10-phenanthroline (12 mol%, 5.0 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) were added to a dry 1.5 mL transparent glass vial, and then 4-(1-benzyloxy)phenyl acetate (0.20 mmol, 48.4 mg), hexafluoroisopropanol (0.15 mL), tert-butyl peroxide (4.0 eq., 0.147 mL), and pyridine (1.0 eq., 0.016 mL) were added in sequence. The mixture was irradiated with 40 W blue light and 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 and eluted with petroleum ether / ethyl acetate (60:1) to obtain 32.1 mg of white solid with a yield of 63%. A mixed solution of petroleum ether / ethyl acetate = 15 / 1 was used as the developing solvent. f =0.31, I-23 was prepared, and its chemical structure is as follows:

[0185]

[0186] 1 H NMR (400 MHz, CDCl 3 )δ7.37-7.30(m, 4H), 7.27-7.23(m, 1H), 6.91-6.87(m, 2H), 6.85-6.80(m, 2H), 5.24(q, J=6.4Hz, 1H), 2.24(s, 3H), 1.62(d, J=6.4Hz, 3H). 13 C NMR (101 MHz, CDCl 3 )δ169.9, 155.8, 144.3, 143.1, 128.8, 127.6, 125.7, 122.3, 116.6, 76.7, 24.6, 21.2.HRMS (ESI): C 16 H 16 NaO 3 [M+Na] + The calculated exact molecular weight is 279.0992 and the measured value is 279.0990.

[0187] Example 24: Preparation of ethyl 1-(2,4-dichlorophenyl)acetate I-24

[0188] In a glove box, tetrapyridine nickel chloride (10 mol%, 9.0 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) were added to a dry 1.5 mL transparent glass vial, and then 1-(2,4-dichlorophenyl)acetic acid methyl ester (0.20 mmol, 43.8 mg), hexafluoroisopropanol (0.15 mL), tert-butyl peroxide (8.0 eq., 0.294 mL) were added in sequence. The mixture was irradiated with 40 W blue light and 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 / ethyl acetate (50:1), and 29.0 mg of colorless oily liquid was obtained with a yield of 62%. A mixed solution of petroleum ether / ethyl acetate = 15 / 1 was used as the developing solvent. f =0.45, I-24 was prepared, and its chemical structure is as follows:

[0189]

[0190] 1 H NMR (400 MHz, CDCl 3 )δ7.39-7.37(m, 1H), 7.27-7.24(m, 1H), 6.15(q, J=6.4Hz, 1H), 2.10(s, 3H), 1.50(d, J=6.4Hz, 3H). 13 C NMR (101 MHz, CDCl 3 )δ169.9, 138.5, 134.1, 132.8, 129.5, 127.7, 127.6, 68.9, 21.3, 21.1.HRMS (ESI): C 10 H 10 Cl 2 NaO 2 [M+Na] + The calculated exact molecular weight is 254.9950 and the measured value is 254.9949.

[0191] Example 25: Preparation of methyl 2-hydroxy-2-phenylpropionate I-25

[0192] In a glove box, tetrapyridine nickel chloride (10 mol%, 9.0 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) were added to a dry 1.5 mL transparent glass vial, and then 2-hydroxy-2-phenylacetic acid methyl ester (0.20 mmol, 33.2 mg), hexafluoroisopropanol (0.15 mL), tert-butyl peroxide (4.0 eq., 0.147 mL) were added in sequence. The mixture was irradiated with 40 W blue light and 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 and eluted with petroleum ether / ethyl acetate (15:1) to obtain 30.2 mg of colorless oily liquid with a yield of 84%. A mixed solution of petroleum ether / ethyl acetate = 8 / 1 was used as the developing solvent. f =0.28, I-25 was prepared, and its chemical structure is as follows:

[0193]

[0194] 1 H NMR (400 MHz, CDCl 3 )δ7.56-7.53(m, 2H), 7.38-7.33(m, 2H), 7.32-7.27(m, 1H), 3.78(s, 3H), 3.74(s, 1H), 1.79(s, 3H). 13 C NMR (101 MHz, CDCl 3 )δ176.2, 142.9, 128.5, 128.0, 125.3, 76.0, 53.3, 26.9.HRMS (ESI): C 10 H 12 NaO 3 [M+Na] + The calculated exact molecular weight is 203.0679 and the measured value is 203.0677.

[0195] Examples 26-29 provide the application of the preparation method to complex drug molecules, as follows:

[0196] Example 26: Preparation of 3-chloro-N-(1-phenylethyl)propionamide I-26

[0197] In a glove box, tetrapyridine nickel chloride (5 mol%, 4.5 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) were added to a dry 1.5 mL transparent glass vial, and then anticonvulsant drug beclamide (0.20 mmol, 39.5 mg), hexafluoroisopropanol (0.16 mL), tert-butyl peroxide (6.0 eq., 0.22 mL) were added in sequence, 40 W blue light was irradiated, and the reaction was reacted at room temperature for 36 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 29.5 mg of white solid was obtained, with a yield of 70%. A mixed solution of petroleum ether / ethyl acetate = 5 / 1 was used as the developing solvent, R f =0.33, I-26 was prepared, and its chemical structure is as follows:

[0198]

[0199] 1 H NMR (400 MHz, CDCl 3 )δ7.37-7.31(m, 4H), 7.29-7.25(m, 1H), 5.90(d, J=4.8Hz, 1H), 5.16(p, J=7 .2Hz, 1H), 3.85-3.75 (m, 2H), 2.62 (t, J=6.8Hz, 2H), 1.51 (d, J=7.2Hz, 3H).

[0200] 13 C NMR (101 MHz, CDCl 3 )δ168.6, 143.0, 128.8, 127.6, 126.3, 49.2, 40.3, 39.9, 21.8.HRMS (ESI): C 11 H 15 ClNO[M+H] + The calculated exact molecular weight is 212.0837 and the measured value is 212.0839.

[0201] Example 27: Preparation of 2-(4-fluoro-3-(trifluoromethyl)phenoxy)-N-(1-phenylethyl)butyramide I-27

[0202] In a glove box, tetrapyridine nickel chloride (5 mol%, 4.5 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) were added to a dry 1.5 mL transparent glass vial, and then the selective herbicide fluazifop (0.20 mmol, 71.1 mg), hexafluoroisopropanol (0.16 mL), and tert-butyl peroxide (6.0 eq., 0.22 mL) were added in sequence. The mixture was irradiated with 40 W blue light and 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 and eluted with petroleum ether / ethyl acetate (10:1) to obtain 47.4 mg of white solid with a yield of 64% and a dr of 1.3:1. A mixed solution of petroleum ether / ethyl acetate = 10 / 1 was used as the developing solvent. f =0.32, I-27 was prepared, and its chemical structure is as follows:

[0203]

[0204] 1 H NMR (400 MHz, CDCl 3 )δ7.37-6.94(m, 8H), 6.51-6.45(m, 1H), 5.20-5.11(m, 1H), 4.50-4.44(m, 1H), 2.05-1.89(m, 2H), 1 .50 (d, J=6.8Hz, 1.7H), 1.41 (d, J=6.8Hz, 1.3H), 1.06 (t, J=7.6Hz, 1.7H), 0.97 (t, J=7.6Hz, 1.3H). 13 C NMR (101 MHz, CDCl 3 )majorδ: 169.9, 154.7 (dm, J=251.9Hz), 153.27 (d, J=2.7Hz), 142.6, 128.8, 127.6, 126.0, 1 22.26 (qd, J=273.6, 1.3Hz), 120.3, 118.2, 118.0, 114.65 (m), 81.3, 48.48, 26.2, 21.7, 9.34 ;minor δ: 169.8, 154.7 (dm, J=251.9Hz), 153.32 (d, J=2.7Hz), 142.7, 128.9, 127.7, 126.2, 1 22.31 (qd, J=273.7, 1.4Hz), 120.2, 118.3, 118.1, 114.63 (m), 81.4, 48.51, 26.1, 21.6, 9.25. 19FNMR (377 MHz, CDCl 3 )δ-61.7 (dd, J=13.2, 4.5Hz), -123.3 (dq, J=58.1, 13.1Hz).HRMS (ESI): C 19 H 20 F 4 NO 2 [M+H] + The calculated exact molecular weight is 370.1425 and the measured value is 370.1427.

[0205] Example 28: Preparation of 4-methoxy-N-(1-(4-trifluoromethylphenyl)ethylbutyramide I-28

[0206] In a glove box, tetrapyridine nickel chloride (5 mol%, 4.5 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) were added to a dry 1.5 mL transparent glass vial, and then the natural neurotransmitter g-hydroxybutyric acid analog GET73 (0.20 mmol, 55.0 mg), hexafluoroisopropanol (0.16 mL), and tert-butyl peroxide (6.0 eq., 0.22 mL) were added in sequence. The mixture was irradiated with 40 W blue light and 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 / ethyl acetate (1:1), and 37.0 mg of colorless oily liquid was obtained with a yield of 64%. A mixed solution of petroleum ether / ethyl acetate = 1 / 2 was used as the developing solvent. f =0.30, I-28 was prepared, and its chemical structure is as follows:

[0207]

[0208] 1 H NMR (400 MHz, CDCl 3 )δ7.53 (d, J=8.4Hz, 2H), 7.38 (d, J=8.0Hz, 2H), 5.09 (q, J=6.8Hz, 1H), 3.38-3.33 (m, 2H), 3.27 (s, 3H), 2.29-2.25 (m, 2H), 1.89-1.82 (m, 2H), 1.42 (d, J=7.2Hz, 3H). 13 C NMR (101 MHz, CDCl 3) δ172.1, 147.9 (q, J = 0.9Hz), 129.4 (q, J = 32.5Hz), 126.4, 125.6 (q, J = 3.7Hz), 124.2 (q, J = 272.9Hz), 71.9, 58.5, 48.4, 33.5, 25.5, 21.9. 19 F NMR (377 MHz, CDCl 3 )δ-62.5.HRMS(ESI):C 14 H 18 F 3 NNaO 2 [M+Na] + The calculated exact molecular weight is 312.1182, and the measured value is 312.1182.

[0209] Example 29: Preparation of N-(1-(4-(2-(dimethylamino)ethoxy)phenyl)ethyl)-3,4-dimethoxybenzamide I-29

[0210] In a glove box, ethylene glycol dimethyl ether nickel chloride (10 mol%, 4.4 mg), 2,9-dimethyl-1,10-phenanthroline (12 mol%, 5.0 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) were added to a dry 1.5 mL transparent glass vial, and then the antiemetic itopride (0.20 mmol, 71.6 mg), hexafluoroisopropanol (0.24 mL), and tert-butyl peroxide (12.0 eq., 0.44 mL) were added in sequence. The mixture was irradiated with 40 W blue light and 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 dichloromethane / methanol (15:1), and 23.5 mg of colorless oily liquid was obtained with a yield of 32%. A mixed solution of dichloromethane / methanol = 10 / 1 was used as the developing solvent. f =0.19, O-29 was prepared, and its chemical structure is as follows:

[0211]

[0212] 1 H NMR (400 MHz, CDCl 3)δ7.42 (s, 1H), 7.31-7.29 (m, 2H), 7.26-7.23 (m, 1H), 6.90-6.88 (m, 2H), 6.83-6.81 (m, 1H), 6.27 (d, J=7.6Hz, 1H), 5.2 6 (p, J=6.8Hz, 1H), 4.10 (t, J=5.4Hz, 2H), 3.90-3.89 (m, 6H), 2.80 (t, J=5.2Hz, 2H), 2.39 (s, 6H), 1.57 (d, J=6.8Hz, 3H).

[0213] 13 C NMR (101 MHz, CDCl 3 )δ166.2, 158.1, 151.9, 149.2, 135.8, 127.6, 119.3, 116.2, 114.9, 110.9, 110.4, 65.8, 58.2, 56.2, 48.8, 46.0, 45.7, 21.7.HRMS (ESI): C 21 H 29 N 2 O 4 [M+H] + The calculated exact molecular weight is 373.2122, and the measured value is 373.2120.

[0214] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the present invention. Although the present invention is described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention can be modified or replaced by equivalents without departing from the purpose and scope of the present technical solutions, which should all be included in the scope of the claims of the present invention. The technical features of the above-mentioned embodiments can be combined arbitrarily. In order to make the description concise, all possible combinations of the technical features in the above-mentioned embodiments are not described. However, as long as there is no contradiction in the combination of these technical features, they should all be considered to be within the scope of this specification.

[0215] The above-described embodiments only express several implementation methods of the present invention, which are convenient for understanding the technical solutions of the present invention in detail, but they cannot be understood as limiting the scope of protection of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. It should be understood that the technical solutions obtained by those skilled in the art through logical analysis, reasoning or limited experiments on the basis of the technical solutions provided by the present invention are all within the protection scope of the claims attached to the present invention. Therefore, the protection scope of the patent of the present invention shall be based on the contents of the attached claims, and the description can be used to interpret the contents of the claims.

Claims

1. A HFIP booster C(sp 3 )-H bond direct methylation synthesis method, characterized in that, The synthetic route of the method is as follows: Wherein, in the general structural formula I of the synthesized α-methylated product, X is N, O or S; the dotted line indicates bonding or non-bonding; R 1 is selected from substituted or unsubstituted aryl having 5 to 40 ring atoms, substituted or unsubstituted heteroaryl having 5 to 40 ring atoms, substituted or unsubstituted C1-C10 alkyl, substituted acyl, substituted alkoxycarbonyl, substituted aryloxycarbonyl, substituted alkylaminocarbonyl, substituted arylaminocarbonyl, substituted alkenyl or substituted alkynyl; R 2 is selected from H, substituted or unsubstituted C1-C10 alkyl, substituted acyl, substituted alkylaminocarbonyl, substituted alkoxycarbonyl, substituted or unsubstituted aryl having 5 to 40 ring atoms, or substituted or unsubstituted heteroaryl having 5 to 40 ring atoms; R 3 Absent or selected from H, substituted acyl, substituted ester, substituted amide or substituted sulfonamide; R 4 is selected from H, D, a substituted or unsubstituted C1-C5 alkyl group, a substituted alkoxycarbonyl group, a substituted alkylaminocarbonyl group or a substituted or unsubstituted aryl group having 5 to 40 ring atoms.

2. The synthesis method according to claim 1, characterized in that The steps include: In an argon or nitrogen atmosphere, a nickel salt catalyst, a ligand, a photocatalyst, a substrate to be methylated, an additive and a solvent are mixed to prepare a first reaction mixture; a methyl 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.

3. The synthesis method according to claim 2, characterized in that Satisfy one or more of the following (1) to (6): (1) The nickel salt catalyst includes one or more of ethylene glycol dimethyl ether nickel chloride, ethylene glycol dimethyl ether nickel bromide, nickel chloride, nickel bromide, nickel acetylacetonate and tetrapyridine nickel chloride; (2) The ligand includes one or more of no additive, 2,9-dimethyl-1,10-phenanthroline, 1,10-phenanthroline, tris(2-pyridylmethyl)amine, 1,3-bi(4-pyridyl)propane, terpyridine, 4,4′-dimethyl-2,2′-bipyridine, 6,6′-dimethyl-2,2′-bipyridine, 4,4′-di-tert-butyl-2,2′-bipyridine, 1,2-bis(diphenylphosphino)ethane and 1,1′-binaphthyl-2,2′-bisdiphenylphosphine; (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 methyl source comprises one or more of tert-butyl peroxide and dicumyl peroxide; (5) The solvent includes one or more of hexafluoroisopropanol, trifluoroethanol and dimethyl sulfoxide;. (6) The additive includes one or more of pyridine and its substituted pyridine derivatives.

4. The preparation method according to claims 1-3, characterized in that: The general structural formula of the substrate to be methylated is shown in the following formula (II): Dashed line, X, R 1 , R 2 , R 3 , R 4 The definition is the same as that of claim 1.

5. The preparation method according to claim 3, characterized in that: Satisfy one or more of the following (1) to (10): (1) The molar percentage of the nickel salt catalyst and the substrate to be methylated is 5% to 20%; (2) The molar percentage of the photocatalyst and the substrate to be methylated is 0.5% to 2%; (3) The molar percentage of the ligand and the substrate to be methylated is 6% to 24%; (4) The molar ratio of the nickel salt catalyst to the photocatalyst is (5-20):1; (5) The molar volume ratio of the substrate to be methylated and the solvent is 1 mol: (0.4-1.2) L; (6) The molar ratio of the additive to the substrate to be methylated is (0.5-2):1; (7) The molar ratio of the methyl source to the substrate to be methylated is (2-12):1; (8) The light source for the photocatalytic reaction includes blue light; (9) The reaction temperature is 15°C to 30°C; (10) The reaction time is 24h to 72h.

6. The HFIP booster C(sp) according to claim 1 3 )-H bond direct methylation synthesis method, characterized in that, The synthesized product is an α-methylamine derivative, and the general structural formula of the α-methylamine derivative is as follows III: R 1 , R 2 , R 3 , R 4 and the dotted line as shown in claim 1; R 1 Including phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl, 2,4-difluorophenyl, 4-trifluoromethylphenyl, 4-cyanophenyl, 4-phenylphenyl, 4-methoxyphenyl, 4-thiomethylphenyl, 4-N,N-dimethylphenyl, 4-tert-butylphenyl, 4-isopropylphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-methoxyphenyl, 3-trifluoromethylphenyl, 3-cyanophenyl phenyl, 2-hydroxyphenyl, 2-acetoxyphenyl, 2-methoxycarbonylphenyl, 2-fluorophenyl, 2-chlorophenyl, 2,2-difluoro[d][1,3]dihydroxybenzocyclopentyl, 2-naphthyl, 1-naphthyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-fluoro-2-pyridyl, 4-trifluoromethyl-2-pyridyl, 5-chloro-2-pyridyl, 3-N-methylindolyl, 2-thienyl, 3-thienyl or 2-quinolyl; R 2 Including H, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 4-cyanophenyl, 4-nitrophenyl, 4-methoxyphenyl, 4-N,N-dimethylphenyl, 4-tert-butylphenyl, 3,4-difluorophenyl, 2-naphthyl, 2-pyridyl, 2-pyrimidyl, 2-quinolyl or 2-isoquinolyl; R 3 Including acetyl, trifluoroacetyl, pivaloyl, cyclohexanoyl, tert-butyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, phenoxycarbonyl, benzenesulfonyl, benzoyl, 4-methoxybenzoyl, 4-tert-butylbenzoyl, 4-fluorobenzoyl, 4-cyanobenzoyl, 2,6-dichlorobenzoyl, 2-pyridoyl, phenylthiocarboyl or phenylaminoyl; R 4 including H, D, methyl, methoxycarbonyl or phenyl; Or the following α-methyl drug molecules and cyclic amine derivatives:

7. The HFIP booster C(sp) according to claim 1 3 )-H bond direct methylation synthesis method, characterized in that, The synthesized products are α-methyl amino acids and dipeptide derivatives, and the general structural formula of the α-methyl amino acids and dipeptide derivatives is as follows IV: R 1 and R 3 As claimed in claim 1; R 1 including methoxycarbonyl, L-valine carbonyl, L-alanine carbonyl, L-leucine carbonyl, L-isoleucine carbonyl or L-phenylalanine carbonyl; R 3 These include acetyl or benzoyl.

8. The HFIP booster C(sp) according to claim 1 3 )-H bond direct methylation synthesis method, characterized in that, The synthesized product is an α-methyl ether / alcohol derivative, and the general structural formula of the α-methyl ether / alcohol derivative is as follows: R 1 , R 2 and R 4 As claimed in claim 1; R 1 including phenyl, 4-cyanophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 3-methoxyphenyl, 4-tert-butylphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 4-trifluoromethylphenyl, benzo-2,2-difluoro[d][1,3]dihydroxycyclopentyl, 2-pyridyl, 4-chloro-2-pyridyl, 6-fluoro-2-pyridyl, 2-quinolyl, 2-naphthyl, 2-thienyl, 3-pyridyl, 4-pyridyl, ethynyl, phenylynyl, ethoxycarbonyl, methoxycarbonyl, isopropyloxycarbonyl or phenoxycarbonyl; R2 includes H, phenyl, 4-fluorophenyl, 4-bromophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 4-cyanophenyl, 4-phenylphenyl, 4-tert-butylphenyl, 4-methoxycarbonylphenyl, 4-acetamidophenyl, 4-acetoxyphenyl, 2-iodophenyl, 2-methoxyphenyl, 3,5-dimethoxyphenyl, 1-naphthyl, 6-quinolyl, 3-methoxycarbonyl-2-naphthyl, methyl, isopropyl, 1-bromo-n-butyl, benzoyloxybutyl, acetyl, pivaloyl, benzoyl, 4-cyanobenzoyl or tert-butyloxycarbonyl; R4 includes H, D, methoxycarbonyl, phenoxycarbonyl, tert-butyloxycarbonyl, phenylaminocarbonyl, tert-butylaminocarbonyl or methylaminocarbonyl.

9. The preparation method according to claim 2, characterized in that: After the photocatalytic reaction, the method further comprises a step of separation by silica gel column chromatography; the eluent of the silica gel column chromatography comprises a mixed solvent of petroleum ether-ethyl acetate, a mixed solvent of petroleum ether-acetone or a mixed solvent of dichloromethane-methanol.

10. The HFIP booster C(sp) according to any one of claims 1 to 9 3 Application of the direct methylation synthesis method of )-H bonds in the field of late derivatization and modification of natural products or candidate drugs.

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