Azetidine trichloroacetimidate as well as preparation method and application thereof

Abstract

The invention relates to the technical field of organic synthesis, in particular to azetidine trichloroacetimidate as well as a preparation method and application thereof, and the azetidine trichloroacetimidate has a structure as shown in a formula I which is described in the specification. The azetidine trichloroacetimidate provided by the invention can be prepared through a simple two-step reaction and one-time purification, carbocation intermediates can be effectively generated under the activation of Lewis acid or Bronsted acid, and the intermediates can be effectively captured by various nucleophilic reagents based on C, N, O, S and P, so that the compound can be used for preparing the azetidine trichloroacetimidate. Thus, the functionalized 3-aryl azetidine is formed. On the basis, the modular synthesis method of the functionalized azetidine is realized.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to an azetidine trichloroacetimidate and a preparation method and application thereof. Background Art

[0002] Azetidine is a small, strained nitrogen-containing heterocycle with various desirable properties for drug development, such as inherent rigidity, enhanced solubility, and improved metabolic stability. In addition, azetidine can also serve as a bioisosteric replacement for pyrrolidine, piperidine, and benzene rings. Currently, the methods for obtaining functionalized azetidines mainly include two pathways: constructing azetidine rings and modifying existing azetidine rings. In particular, the direct installation of azetidine rings onto lead compounds has proven to be an extremely attractive approach. For example, the Baran group proposed a novel method based on 2e - The MacMillan group reported a tension release strategy based on 1e - The radical deoxygenation coupling strategy of the process. Both methods can conveniently synthesize 3-monosubstituted azetidines. The Carreira group was the first to use the acceptor azetidine for the addition of nucleophiles, and the electron withdrawing group (EWG) in the product enabled it to be further derivatized. This strategy provides a method to efficiently obtain functionalized 3-alkylazetidines. The Bull group studied 3-aryl azetidinols as azetidinylating agents. In their study, electron-rich aromatic groups were required for the reaction, and the coupling objects were limited to electron-rich aromatics, primary and secondary alcohols, and electron-deficient phenols.

[0003] Therefore, it is of great research value to develop a more general and practical method to obtain functionalized 3-aryl azetidines. Summary of the invention

[0004] In view of this, the technical problem to be solved by the present invention is to provide an azetidine trichloroacetimidate and a preparation method and application thereof. The prepared azetidine trichloroacetimidate can generate a carbon cation intermediate and further form a functionalized 3-aryl azetidine.

[0005] The present invention provides an azetidine trichloroacetimidate having a structure shown in Formula I:

[0006]

[0007] wherein R is selected from substituted or unsubstituted alkyl, alkenyl, aryl or heteroaryl;

[0008] PG is an amino protecting group.

[0009] Preferably, R is a substituted or unsubstituted C1-C20 alkyl group, C2-C20 alkenyl group, C6-C20 aryl group or C4-C20 heteroaryl group.

[0010] More preferably, R is a substituted or unsubstituted C1-C10 alkyl group, C2-C10 alkenyl group, C6-C12 aryl group or C4-C12 heteroaryl group.

[0011] More preferably, R is a substituted or unsubstituted C1-C6 alkyl group, a C2-C6 alkenyl group, a monocyclic aromatic group, a condensed aromatic group of 2 to 3 aromatic groups, a monocyclic heteroaromatic group, or a condensed heteroaromatic group of 2 to 3 rings.

[0012] The above-mentioned monocyclic heteroaryl group is preferably a five-membered or six-membered heteroaryl group.

[0013] The heteroatoms of the heteroaryl group include, but are not limited to, one or more of O, S, N, Si and the like.

[0014] The ring forming the fused heteroaryl group includes a five-membered or six-membered heteroaryl group, or includes a five-membered or six-membered heteroaryl group and an aryl group.

[0015] More preferably, R is substituted or unsubstituted C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C2 alkenyl, C3 alkenyl, C4 alkenyl, C5 alkenyl, C6 alkenyl, phenyl, naphthyl, pyridyl, benzofuranyl, or thienyl.

[0016] In some specific embodiments of the present invention, R is substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, vinyl, propenyl, butenyl, phenyl, naphthyl, pyridyl, benzofuranyl or thienyl.

[0017] The present invention has no particular limitation on the substituent group of R, which may be an electron-withdrawing group or an electron-donating group.

[0018] Preferably, the substituent of R is selected from one or more of halogen, nitro, cyano, hydroxyl, amino, substituted or unsubstituted alkyl, alkoxy, acyl, aryl, heteroaryl, oxaborane group, and sulfonyl group.

[0019] More preferably, the substituent of R is selected from one or more of halogen, nitro, cyano, hydroxyl, amino, substituted or unsubstituted C1-C10 alkyl, C1-C10 alkoxy, C1-C10 acyl, C6-C12 aryl, C4-C12 heteroaryl, oxaborane group, and sulfonyl.

[0020] Further preferably, the substituent of R is selected from one or more of halogen, nitro, cyano, hydroxyl, amino, substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 acyl, phenyl, pyridyl, thienyl, oxaborane group, and sulfonyl.

[0021] In the substituent groups, the alkyl, alkoxy and acyl groups may be further substituted by one or more of the following secondary substituent groups: halogen, nitro, cyano, hydroxyl, amino, alkoxy and alkyl.

[0022] Preferably, in the substituent group, the alkyl, alkoxy and acyl groups may be further substituted by one or more of the following secondary substituent groups: halogen, nitro, cyano, hydroxyl, amino, C1-C10 alkoxy and C1-C10 alkyl.

[0023] Preferably, in the substituent group, the alkyl group, alkoxy group and acyl group may be further substituted by one or more of the following secondary substituent groups: fluorine, chlorine or bromine.

[0024] In some specific embodiments of the present invention, the substituent of R is selected from one or more of halogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, formyl, and trifluoroformyl.

[0025] The PG can be an amino protecting group well known to those skilled in the art, including but not limited to diphenylmethyl, benzyloxycarbonyl or tert-butyloxycarbonyl.

[0026] Preferably, the azetidine trichloroacetimidate has any of the following structures:

[0027]

[0028] The present invention provides a method for preparing the above-mentioned azetidine trichloroacetimidate, comprising the following steps:

[0029] S1) using RY and azetidin-3-one as raw materials, performing a nucleophilic addition reaction to obtain the azetidinol represented by formula Ⅰ-a;

[0030] S2) reacting the azetidine alcohol represented by formula Ⅰ-a with trichloroacetonitrile to obtain the azetidine trichloroacetimidate represented by formula Ⅰ;

[0031]

[0032]

[0033] Wherein, Y is halogen or hydrogen.

[0034] Y can be Br, Cl, I or hydrogen, preferably Br or hydrogen.

[0035] R is selected from substituted or unsubstituted alkyl, alkenyl, aryl or heteroaryl;

[0036] PG is an amino protecting group.

[0037] The ranges of R and PG are the same as above and will not be repeated here.

[0038] Preferably, the nucleophilic addition reaction in step S1) is carried out under the action of an alkyl metal compound.

[0039] The alkyl metal compound is preferably one or more of n-butyl lithium and isopropyl magnesium chloride.

[0040] The solvent for the nucleophilic addition reaction is preferably one or more of tetrahydrofuran and diethyl ether.

[0041] The temperature of the nucleophilic addition reaction is preferably -78 to 25°C, and the time is preferably 2 to 12 hours.

[0042] The nucleophilic addition reaction is preferably carried out in an inert gas atmosphere, and the inert gas is preferably nitrogen.

[0043] Preferably, after the nucleophilic addition reaction is completed, an aqueous solution of ammonium chloride is added to quench the reaction to obtain azetidine alcohol.

[0044] After obtaining the azetidinol, the aqueous layer is extracted with an organic solvent, and the solvent is removed to obtain a product which can be used in the next reaction without further purification.

[0045] The molar ratio of RY to azetidine-3-one is preferably 1:1 to 1.2:1.

[0046] The molar ratio of the alkyl metal compound to azetidin-3-one is preferably 1.2:1 to 2.4:1.

[0047] Preferably, the reaction in step S2) is carried out under the catalysis of a basic compound.

[0048] The basic compound is preferably any one or more of 1,8-diazabicyclo(5,4,0)-7-undecene (DBU), potassium carbonate, cesium carbonate and sodium hydride.

[0049] The reaction solvent in step S2) is preferably one or more of dichloromethane, tetrahydrofuran, 1,4-dioxane, and acetonitrile.

[0050] The reaction temperature of step S2) is preferably 0-25°C, and the reaction time is preferably 0.5-12h.

[0051] The reaction is preferably carried out in an inert gas atmosphere, and the inert gas is preferably nitrogen.

[0052] The molar ratio of azetidinol to trichloroacetonitrile is preferably 1:(1-4).

[0053] The molar ratio of the azetidinol to the basic compound is preferably 1:(0.2-2).

[0054] After the reaction is completed, the solvent in the system is removed, and the crude product is directly purified by silica gel or neutral alumina column chromatography to obtain azetidine trichloroacetimidate.

[0055] In some specific embodiments of the present invention, the above reaction equation is as follows:

[0056]

[0057] The method provided by the present invention does not require expensive transition metal catalysis, uses low-priced azetidin-3-one with different protective groups as a starting material, and performs a nucleophilic addition reaction in the presence of n-butyl lithium to generate a 3-aryl azetidinol intermediate. Subsequently, the 3-aryl azetidinol and trichloroacetonitrile are converted into various azetidin trichloroacetimidates (ATAs) under the catalysis of DBU, which can be prepared by only a simple two-step reaction and one purification, greatly reducing the cost of the product.

[0058] The azetidine trichloroacetimidate prepared by the invention can be coupled with various nucleophilic reagents under the activation of Lewis acid or Bronsted acid to serve as a bioisostere of pyrrolidine, piperidine and benzene ring, and has the advantages of mild reaction conditions, low cost, easy operation, high yield, easy promotion and high product added value.

[0059] The above-mentioned Lewis acid or Bronsted acid is preferably one or more of Cu(OTf)2, bismuth trifluoromethanesulfonate, ferric chloride, boron trifluoride etherate, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid and the like.

[0060] Based on this, the present invention provides a method for preparing a functionalized 3,3-disubstituted azetidine compound, comprising the following steps:

[0061] S1) using RY and azetidin-3-one as raw materials, performing a nucleophilic addition reaction to obtain the azetidinol represented by formula Ⅰ-a;

[0062] S2) reacting the azetidine alcohol represented by formula Ⅰ-a with trichloroacetonitrile to obtain the azetidine trichloroacetimidate represented by formula Ⅰ;

[0063] S3) reacting the azetidine trichloroacetimidate of formula I with a nucleophilic reagent to obtain a functionalized 3,3-disubstituted azetidine compound of formula II;

[0064]

[0065]

[0066] Wherein, Y is halogen or hydrogen;

[0067] R is a substituted or unsubstituted alkyl, alkenyl, aryl or heteroaryl group;

[0068] PG is an amino protecting group.

[0069] Nu is a nucleophile.

[0070] The ranges of Y, R, and PG are the same as above and will not be repeated here.

[0071] The scope of the above steps S1) and S2) is the same as above and will not be repeated here.

[0072] The present invention has no particular limitation on the types of the above-mentioned nucleophilic reagents, and can be nucleophilic reagents containing one or more of the elements C, N, O, S, and P that are well known to those skilled in the art, including but not limited to one or more of compounds containing hydroxyl, thiol, amino, carboxyl, phosphorus-hydrogen bonds, phosphorus-oxyl groups, heterocyclic compounds, heteroaromatic compounds, trimethylsilyl cyanide, enol silyl ethers, indoles, and allyl tributyltin compounds.

[0073] The hydroxyl-containing compound is preferably a C1-C10 alkyl primary, secondary or tertiary alcohol, phenol or the like.

[0074] The thiol-containing compound is preferably a thiol-containing aromatic compound or a heteroaromatic compound. The aromatic compound is preferably a monocyclic aromatic compound, a fused aromatic compound with 1 to 3 monocyclic aromatic groups fused together; the heteroaromatic compound is preferably a five-membered or six-membered monocyclic heterocyclic compound, a fused heteroaromatic compound with 1 to 3 rings fused together. The rings forming the fused heteroaromatic compound include a five-membered or six-membered heteroaromatic compound, or include a five-membered or six-membered heteroaromatic compound and a monocyclic aromatic group. In some specific embodiments of the present invention, the thiol-containing compound is selected from 2-mercaptobenzothiazole.

[0075] The amino group-containing compound is preferably an alkylamine compound or an aromatic amine compound, more preferably a C1-C10 alkylamine compound, diphenylamine, aniline, aminopyridine, benzenesulfonamide, tert-butyl carbamate, dimethyl sulfoxide, benzophenone imine, and the like.

[0076] The carboxyl group-containing compound is preferably C1-C10 alkyl carboxylic acid, benzoic acid, cyclopentanoic acid, or the like.

[0077] The above-mentioned compounds containing phosphorus hydrogen bonds and phosphorus oxygen groups include but are not limited to diphenylphosphine oxide and the like.

[0078] The heterocyclic compound or heteroaromatic compound is preferably a heterocyclic compound or heteroaromatic compound containing N atoms, and the number of the N atoms is preferably 1 to 4.

[0079] The heterocyclic compound may also include one or more heteroatoms such as O, S, Si, etc. It is preferably a five-membered or six-membered monocyclic heterocyclic compound, an N-containing spirocyclic compound, or a fused heterocyclic compound with 1 to 3 rings fused. The N-containing spirocyclic compound is preferably a C1 to C10 N-containing spirocyclic compound, more preferably a C1 to C6 N-containing spirocyclic compound. In some specific embodiments of the present invention, the heterocyclic compound is selected from morpholine, piperidine, 2-oxa-6-aza-spiro[3,3]heptane, etc.

[0080] The heteroaromatic ring compound is preferably a five-membered or six-membered heteroaromatic ring compound, or a fused heteroaromatic ring compound with 1 to 3 rings fused. The rings forming the fused heteroaromatic ring compound include a five-membered or six-membered heteroaromatic ring compound, or include a five-membered or six-membered heteroaromatic ring compound and a monocyclic aromatic group. In some specific embodiments of the present invention, the heteroaromatic ring compound is a substituted or unsubstituted pyrazole, indazole, pyrazolopyridine, benzimidazole, carbazole, benzotriazole, tetrazole, purine, indole, etc.

[0081] Preferably, the above-mentioned compounds containing hydroxyl, thiol, amino, carboxyl, phosphorus-hydrogen bond, phosphorus-oxyl group, heterocyclic compounds, and heteroaromatic ring compounds may further contain secondary substituents such as halogen, cyano, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, phenyl, and boric acid pinacol ester.

[0082] In some specific embodiments of the present invention, the nucleophilic agent includes but is not limited to 4-bromopyrazole, 3-phenyl-1-propylamine, morpholine, 2-oxa-6-aza-spiro[3,3]heptane, piperidine, aniline, 4-aminophenylboronic acid pinacol ester, 4-aminopyridine, N-methylaniline, 6-bromoindazole, 6-chloro-1 hydrogen-pyrazolo[3,4-B]pyridine, 2-phenylbenzimidazole, 3-bromocarbazole, 1,2,3-benzotriazole, 5-phenyltetrazole, purine, 4-(trifluoromethoxy)benzenesulfonamide, tert-butyl carbamate, dimethyl sulfoxide, benzophenone imine, benzoic acid, 1-phenylcyclopentanecarboxylic acid, cedarwood, phenol, 2-mercaptobenzothiazole, diphenylphosphine oxide, trimethylsilyl cyanide, N-methylindole, allyltributyltin, tert-butyldimethyl(1-phenylvinyloxy)silane, 2-methylfuran, etc.

[0083] Preferably, in step S3), the azetidine trichloroacetimidate shown in formula I is activated by Lewis acid or Bronsted acid and then reacted with a nucleophilic reagent.

[0084] The equation for the above reaction is as follows:

[0085]

[0086] Compared with the prior art, the present invention provides an azetidine trichloroacetimidate having a structure shown in formula I.

[0087] The azetidinyl trichloroacetimidates (ATAs) provided by the present invention can be prepared through a simple two-step reaction and a single purification. Under the activation of Lewis acid or Bronsted acid, ATAs can effectively generate carbon cation intermediates, and these intermediates can be effectively captured by various nucleophiles based on C, N, O, S, and P to form functionalized 3-aryl azetidines. Based on this, the present invention realizes a modular synthesis method for functionalized azetidines. BRIEF DESCRIPTION OF THE DRAWINGS

[0088] Figure 1 is the H NMR spectrum of compound 41 (500 MHz, CDCl3);

[0089] Figure 2 is the NMR carbon spectrum of compound 41 (126MHz, CDCl3);

[0090] Figure 3 is the H NMR spectrum of compound 42 (500 MHz, CDCl3);

[0091] Figure 4 This is the carbon NMR spectrum of compound 42 (126 MHz, CDCl3). DETAILED DESCRIPTION

[0092] In order to further illustrate the present invention, the following is a detailed description in conjunction with the embodiments. However, it should be understood that these descriptions are only for further illustrating the features and advantages of the present invention, rather than limiting the claims of the invention.

[0093] All raw materials of the present invention are not particularly limited in their sources and can be purchased from the market or prepared according to conventional methods well known to those skilled in the art.

[0094] Example 1 Preparation of ATA-1:

[0095]

[0096] Under a nitrogen atmosphere, n-butyl lithium (1.2 equiv.) was added dropwise to a solution (0.5 M) of anhydrous tetrahydrofuran of the aryl bromide 1-bromo-4-methoxybenzene (12 mmol, 2.24 g, 1.2 equiv.) and stirred at -78°C for 1 hour. Then, a solution of azetidin-3-one (1.0 equiv.) in tetrahydrofuran with a CHPh2 protective group was slowly added dropwise to the reaction mixture. The mixture continued to stir at -78°C for 10 minutes, then naturally returned to room temperature and reacted overnight. After the reaction was completed, a saturated NH4Cl aqueous solution was added to quench the reaction. The aqueous layer was extracted 3 times with ethyl acetate, and the combined organic layers were then washed with brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain a crude product, 3-(4-methoxyphenyl)azetidinol.

[0097] Under nitrogen atmosphere at 0°C, DBU (20 mol%) was added to a solution of crude 3-(4-methoxyphenyl)azetidinol (1.0 equiv., assumed to be 100% pure) and trichloroacetonitrile (4.0 equiv.) in anhydrous dichloromethane (0.4 M), and the mixture was slowly warmed to room temperature and stirred for 2 hours. After the reaction was completed, the solvent was removed by reduced pressure, and the crude product was purified by neutral alumina column chromatography to obtain azetidine trichloroacetimidate ATA-1 (3.95 g, 81% yield) as a white solid with a purity of more than 90%.

[0098] 1 H NMR (500MHz, CDCl3): δ8.22(s,1H),7.65(d,J=8.9Hz,2H),7.50(d,J=7.5Hz,4H),7.31(t,J=7.6Hz,4 H),7.22(t,J=7.3Hz,2H),7.04–6.94(m,2H),4.53(s,1H),3.98–3.70(m,5H),3.50(d,J=9.6Hz,2H).

[0099] 13 C NMR (126MHz, CDCl3): δ159.2,142.1,132.8,128.6,127.5,127.3,126.5,113.8,91.6,78.6,78.2,65.2,55.3.

[0100] HRMS(ESI-TOF)m / z:calc'd for C 25 H 24 Cl3N2O2[M+H] + :489.0898; found489.0911.

[0101] Example 2 Preparation of ATA-2

[0102]

[0103] Use 1-bromo-4-fluorobenzene (12 mmol, 2.08 g) to prepare according to the above steps and purify by silica gel column chromatography to obtain the desired compound ATA-2 (4.19 g, yield 88%) as a white solid with a purity of more than 90%.

[0104] 1 H NMR (500MHz, CDCl3): δ8.19(s,1H),7.76–7.60(m,2H),7.54–7.41(m,4H),7.26(t,J=7.6Hz,4H),7 .21–7.14(m,2H),7.09(t,J=8.7Hz,2H),4.48(s,1H),3.80(d,J=9.8Hz,2H),3.45(d,J=9.6Hz,2H).

[0105] 13 C NMR (126MHz, CDCl3): δ162.4 (d, J = 246.4Hz), 159.1, 141.9, 136.6 (d, J = 3.2Hz), 128 .7,127.5,127.4,126.9(d,J=7.8Hz),115.4(d,J=21.6Hz),91.4,78.3,78.2,65.2.

[0106] 19 F NMR (471MHz, CDCl3): δ-114.69.

[0107] HRMS(ESI-TOF)m / z:calc'd for C 24 H 21 Cl3FN2O[M+H] + :477.0698; found477.0689.

[0108] Example 3 Preparation of ATA-3

[0109]

[0110] Use 1-bromo-4-chlorobenzene (12 mmol, 2.30 g) to prepare according to the above steps and purify by silica gel column chromatography to obtain the desired compound ATA-3 (3.20 g, yield 65%) as a white solid with a purity of more than 90%.

[0111] 1H NMR (500MHz, CDCl3): δ8.21 (s, 1H), 7.64 (d, J = 8.5Hz, 2H), 7.49–7.42 (m, 4H), 7.44–7.36 (m, 2H), 7.31–7.27(m,4H),7.22–7.17(m,2H),4.49(s,1H),3.80(d,J=9.5Hz,2H),3.44(d,J=9.5Hz,2H).

[0112] 13 C NMR (126MHz, CDCl3): δ159.1,141.8,139.5,133.7,128.8,128.7,127.5,127.5,126.4,91.3,78.2,78.1,65.1.

[0113] HRMS(ESI-TOF)m / z:calc'd for C 24 H 21 Cl4N2O[M+H] + :493.0403; found493.0405.

[0114] Example 4 Preparation of ATA-4

[0115]

[0116] Use 1-bromo-4-methylbenzene (12 mmol, 2.05 g) to prepare according to the above steps and purify by neutral alumina column chromatography to obtain the desired compound ATA-4 (2.41 g, yield 51%) as a white solid with a purity of more than 90%.

[0117] 1 H NMR (400MHz, CDCl3): δ8.22(s,1H),7.63(d,J=8.3Hz,2H),7.50(dd,J=8.1,1.4Hz,4H),7.34–7.27 (m,6H),7.25–7.19(m,2H),4.54(s,1H),3.88(d,J=9.5Hz,2H),3.49(d,J=9.5Hz,2H),2.41(s,3H).

[0118] 13 C NMR (101MHz, CDCl3): δ159.2,142.1,137.9,137.5,129.3,128.6,127.5,127.3,124.9,91.5,78.7,78.2,65.2,21.3.

[0119] HRMS(ESI-TOF)m / z:calc'd for C 25 H 24 Cl3N2O[M+H] + :473.0949; found473.0938.

[0120] Example 5 Preparation of ATA-5

[0121]

[0122] Use 1-bromo-4-(trifluoromethoxy)benzene (12mmol, 2.90g) to prepare according to the above steps and purify by silica gel column chromatography to obtain the desired compound ATA-5 (3.36g, yield 62%) as a white solid with a purity of more than 90%.

[0123] 1 H NMR (400MHz, CDCl3): δ8.26(s,1H),7.79–7.68(m,2H),7.52–7.44(m,4H),7.35–7.25 (m,6H),7.26–7.17(m,2H),4.52(s,1H),3.84(d,J=9.5Hz,2H),3.48(d,J=9.5Hz,2H).

[0124] 13 C NMR (101MHz, CDCl3): δ159.1, 148.8 (q, J = 1.8Hz), 141.8, 139.6, 128.7, 127.5, 126.4, 120.9, 120.6 (q, J = 257.1Hz), 91.3, 78.2, 78.1, 65.3.

[0125] 19 F NMR (376 MHz, CDCl3): δ-57.66.

[0126] HRMS(ESI-TOF)m / z:calc'd for C 25 H 21 Cl3F3N2O2[M+H] + :543.0615; found543.0622.

[0127] Example 6 Preparation of ATA-6

[0128]

[0129] Use 1,4-dibromobenzene (12 mmol, 2.83 g) to prepare according to the above steps and purify by silica gel column chromatography to obtain the desired compound ATA-6 (3.16 g, yield 59%) as a white solid with a purity of more than 90%.

[0130] 1 H NMR (400MHz, CDCl3): δ8.22(s,1H),7.63–7.52(m,4H),7.46(dd,J=8.3,1.4Hz,4H),7.33– 7.25(m,4H),7.24–7.17(m,2H),4.50(s,1H),3.80(d,J=9.5Hz,2H),3.44(d,J=9.5Hz,2H).

[0131] 13 C NMR (101MHz, CDCl3): δ159.1,141.8,140.0,131.7,128.7,127.5,127.5,126.7,121.8,91.3,78.2,78.2,65.1.

[0132] HRMS(ESI-TOF)m / z:calc'd for C 24 H 21 BrCl3N2O[M+H] + :536.9897; found536.9881.

[0133] Example 7 Preparation of ATA-7

[0134]

[0135] Use 2-bromonaphthalene (12 mmol, 2.48 g) to prepare according to the above steps and purify by silica gel column chromatography to obtain the desired compound ATA-7 (4.06 g, yield 80%) as a white solid with a purity of more than 90%.

[0136] 1 H NMR (500MHz, CDCl3): δ8.24(s,1H),8.17(d,J=2.0Hz,1H),7.98–7.81(m,4H),7.56–7.48(m,6H),7.3 3(t,J=7.7Hz,4H),7.24(t,J=7.4Hz,2H),4.59(s,1H),4.01(d,J=9.8Hz,2H),3.60(d,J=9.8Hz,2H).

[0137] 13C NMR (126MHz, CDCl3): δ159.2,142.0,138.0,133.1,133.0,128.7,128.5,128 .5,127.8,127.5,127.4,126.3,126.2,124.1,123.2,91.5,78.9,78.2,65.1.

[0138] HRMS(ESI-TOF)m / z:calc'd for C 28 H 24 Cl3N2O[M+H] + :509.0949; found509.0955.

[0139] Example 8 Preparation of ATA-8

[0140]

[0141] Use 1-bromo-2-toluene (12 mmol, 2.05 g) to prepare according to the above steps and purify by neutral alumina column chromatography to obtain the desired compound ATA-8 (1.13 g, yield 24%) as a white solid with a purity of more than 90%.

[0142] 1 H NMR (500MHz, CDCl3): δ8.09(s,1H),7.64(d,J=9.3Hz,1H),7.42(d,J=7.9Hz,4H),7.29–7.22(m,6 H),7.20–7.14(m,3H),4.46(s,1H),3.98(d,J=10.1Hz,2H),3.67(d,J=10.1Hz,2H),2.33(s,3H).

[0143] 13 C NMR (126MHz, CDCl3): δ159.2,142.1,137.4,136.2,131.6,129.1,128.6,128.6,127.6,127.4,124.8,91.8,80.6,78.2,63.3,20.0.

[0144] HRMS(ESI-TOF)m / z:calc'd for C 25 H 24 Cl3N2O[M+H] + :473.0949; found473.0938.

[0145] Example 9 Preparation of ATA-9

[0146]

[0147] Use 3-bromopyridine (12 mmol, 1.89 g) to prepare according to the above steps and purify by silica gel column chromatography to obtain the desired compound ATA-9 (0.78 g, yield 17%) as a red oil with a purity of more than 90%.

[0148] 1 H NMR (500MHz, CDCl3): δ9.01(s,1H),8.60(s,1H),8.26(s,1H),7.99(dt,J=7.9,1.9Hz,1H),7.49–7.44(m,4H),7.40 –7.33(m,1H),7.29(t,J=7.6Hz,4H),7.24–7.17(m,2H),4.51(s,1H),3.85(d,J=9.6Hz,2H),3.47(d,J=9.6Hz,2H).

[0149] 13 C NMR (126MHz, CDCl3): δ159.0,149.1,146.9,141.7,136.5,132.7,128.7,127.5,127.5,123.4,91.1,78.1,77.1,65.0.

[0150] HRMS(ESI-TOF)m / z:calc'd for C 23 H 21 Cl3N3O[M+H] + :460.0745; found460.0755.

[0151] Example 10 Preparation of ATA-10

[0152]

[0153] The above steps were used to prepare p-bromotrifluorotoluene (12 mmol, 2.70 g) and purified by silica gel column chromatography to obtain the desired compound ATA-10 (3.58 g, yield 68%) as a white solid with a purity of more than 90%.

[0154] 1H NMR (500MHz, CDCl3): δ8.25 (s, 1H), 7.84 (d, J = 8.4Hz, 2H), 7.70 (d, J = 8.5Hz, 2H), 7.46 (dd, J = 8.2, 1.4Hz, 4H),7.29(t,J=7.6Hz,4H),7.24–7.18(m,2H),4.51(s,1H),3.82(d,J=9.6Hz,2H),3.47(d,J=9.6Hz,2H).

[0155] 13 C NMR (126MHz, CDCl3): δ159.1, 145.0, 141.7, 130.0 (q, J = 32.6Hz), 128.7, 127.5, 127.5, 125.7 (q, J = 3.9Hz), 125.1, 124.3 (q, J = 273.4Hz), 91.2, 78.2, 78.1, 65.2.

[0156] 19 F NMR (471 MHz, CDCl3): δ-62.50.

[0157] HRMS(ESI-TOF)m / z:calc'd for C 25 H 21 Cl3F3N2O[M+H] + :527.0666; found527.0685.

[0158] Example 11 Preparation of ATA-11

[0159]

[0160] Bromobenzene (12 mmol, 1.88 g) was used to prepare according to the above steps and purified by silica gel column chromatography to obtain the desired compound ATA-11 (3.44 g, yield 75%) as a light yellow solid with a purity of more than 90%.

[0161] 1 H NMR (500MHz, CDCl3): δ8.22(s,1H),7.72(d,J=7.9Hz,2H),7.51–7.43(m,6H),7.38–7.33(m,1H),7 .30(t,J=7.6Hz,4H),7.22–7.19(m,2H),4.52(s,1H),3.87(d,J=9.6Hz,2H),3.48(d,J=9.6Hz,2H).

[0162] 13C NMR (126MHz, CDCl3): δ159.1,142.0,140.9,128.6,128.6,127.8,127.5,127.4,124.8,91.4,78.7,78.2,65.2.

[0163] HRMS(ESI-TOF)m / z:calc'd for C 24 H 22 Cl3N2O[M+H] + :459.0792; found459.0780.

[0164] Example 12 Preparation of ATA-12

[0165]

[0166] Use 1-bromo-3-isopropylbenzene (12 mmol, 2.39 g) to prepare according to the above steps and purify by neutral alumina column chromatography to obtain the desired compound ATA-12 (3.50 g, yield 70%) as an oil with a purity of more than 90%.

[0167] 1 H NMR (500MHz, CDCl3): δ8.22(s,1H),7.62–7.55(m,2H),7.54–7.47(m,4H),7.40(t,J=7.6Hz,1H),7.33–7.29(m,4H),7.26 –7.18(m,3H),4.54(s,1H),3.88(d,J=9.6Hz,2H),3.50(d,J=9.5Hz,2H),2.98(hept,J=6.9Hz,1H),1.30(d,J=6.9Hz,6H).

[0168] 13 C NMR (126MHz, CDCl3): δ159.1,149.0,142.1,140.7,128.6,128.4,127.5,127.4,126.0,122.8,122.4,91.6,78.9,78.2,65.2,34.3,24.1.

[0169] HRMS(ESI-TOF)m / z:calc'd for C 27 H 27 Cl3N2NaO[M+Na] + :523.1081; found523.1098.

[0170] Example 13 Preparation of ATA-13

[0171]

[0172] Use bromobenzene (12 mmol, 1.88 g) to prepare according to the above steps, replace the azetidine-3-one with a CHPh2 protecting group with an azetidine-3-one with a Cbz protecting group, and purify by silica gel column chromatography to obtain the desired compound ATA-13 (1.62 g, yield 38%) as a white solid with a purity of more than 90%.

[0173] 1 H NMR (400MHz, CDCl3): δ8.40 (s, 1H), 7.56–7.46 (m, 2H), 7.45–7.32 (m, 8H), 5.16 (s, 2H), 4.55 (d, J = 11.0Hz, 2H), 4.48 (d, J = 11.0Hz, 2H).

[0174] 13 C NMR (101MHz, CDCl3): δ159.1,156.5,139.0,136.4,128.8,128.6,128.4,128.3,128.2,124.7,91.0,79.3,67.1,61.3.

[0175] HRMS(ESI-TOF)m / z:calc'd for C 19 H 17 Cl3N2NaO3[M+Na] + :449.0197; found449.0193.

[0176] Example 14 Preparation of ATA-14

[0177]

[0178] Use bromobenzene (12 mmol, 1.88 g) to prepare according to the above steps, replace the azetidine-3-one with a CHPh2 protecting group with an azetidine-3-one with a Boc protecting group, and purify by silica gel column chromatography to obtain the desired compound ATA-14 (2.98 g, yield 79%) as a white solid with a purity of more than 90%.

[0179] 1H NMR (400MHz, CDCl3): δ8.39(s,1H),7.59–7.46(m,2H),7.46–7.37(m,2H),7. 37–7.31(m,1H),4.45(d,J=10.0Hz,2H),4.38(d,J=10.0Hz,2H),1.48(s,9H).

[0180] 13 C NMR (101MHz, CDCl3): δ159.1,156.4,139.3,128.7,128.3,124.8,91.1,80.3,79.1,60.7,28.5.

[0181] HRMS(ESI-TOF)m / z:calc'd for C 16 H 19 Cl3N2NaO3[M+Na] + :415.0353; found415.0364.

[0182] Example 15 Preparation of ATA-15

[0183]

[0184] Use 1-bromo-2-isopropylbenzene (12 mmol, 2.39 g) to prepare according to the above steps and purify by neutral alumina column chromatography to obtain the desired compound ATA-15 (0.99 g, yield 23%) as a white solid with a purity of more than 90%.

[0185] 1 H NMR (500MHz, CDCl3): δ8.30(s,1H),7.63–7.58(m,1H),7.40–7.32(m,2H),7.25–7.15(m,1H),4.60(d, J=10.1Hz,2H),4.54(d,J=10.1Hz,2H),3.05(hept,J=6.7Hz,1H),1.45(s,9H),1.25(d,J=6.7Hz,6H).

[0186] 13 C NMR (126MHz, CDCl3): δ159.4,156.3,148.8,133.7,130.0,129.5,127.2,124.7,91.3,80.9,80.2,60.1,29.4,28.5,24.8.

[0187] HRMS(ESI-TOF)m / z:calc'd for C19 H 26 Cl3N2O3[M+H] + :435.1004; found435.1015.

[0188] Example 16 Preparation of ATA-16

[0189]

[0190] Under a nitrogen atmosphere, a tetrahydrofuran solution of vinylmagnesium bromide (1.0M, 1.2equiv.) was added dropwise to an anhydrous tetrahydrofuran solution (0.5M) of tert-butyl 3-oxoazetidine-1-carboxylate (10mmol, 1.0equiv.). The mixture was stirred at -20 °C for 10 minutes, then naturally returned to room temperature and reacted overnight. After the reaction was completed, a saturated NH4Cl aqueous solution was added to quench the reaction. The aqueous layer was extracted 3 times with ethyl acetate, and the combined organic layer was then washed with brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain a crude product of tert-butyl 3-hydroxy-3-vinylazetidine-1-carboxylate.

[0191] Under nitrogen atmosphere at 0°C, DBU (20 mol%) was added to a solution of crude product tert-butyl 3-hydroxy-3-vinylazetidine-1-carboxylate (1.0 equiv., assumed to be 100% pure) and trichloroacetonitrile (4.0 equiv.) in anhydrous dichloromethane (0.4 M), and the mixture was slowly warmed to room temperature and stirred for 2 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the crude product was directly purified by silica gel column chromatography to obtain the desired compound ATA-16 (3.08 g, 90% yield) as a white solid with a purity of more than 90%.

[0192] 1 H NMR (500MHz, CDCl3): δ8.43(s,1H),6.22(dd,J=17.5,11.0Hz,1H),5.44(d,J=17.4Hz,1 H), 5.33 (d, J = 11.0Hz, 1H), 4.25 (d, J = 10.8Hz, 2H), 4.12 (d, J = 11.0Hz, 2H), 1.44 (s, 9H).

[0193] 13 C NMR (126MHz, CDCl3): δ159.6,156.4,135.8,116.3,91.1,80.2,77.9,60.1,28.5.

[0194] HRMS(ESI-TOF)m / z:calc'd for C 12 H 17Cl3N2NaO3[M+Na] + :365.0197; found365.0208.

[0195] Example 17 Preparation of ATA-17

[0196]

[0197] Under nitrogen atmosphere, n-butyl lithium (2.5M, 1.2equiv.) in n-hexane was added dropwise to a solution of 1-dibenzyl azetidine-3-one (10mmol, 1.0equiv.) in anhydrous tetrahydrofuran (0.5M). The mixture was stirred at -78°C for 10 minutes, then naturally returned to room temperature and reacted overnight. After the reaction was completed, a saturated NH4Cl aqueous solution was added to quench the reaction. The aqueous layer was extracted 3 times with ethyl acetate, and the combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain a crude product of 1-dibenzyl-3-butylazetidine-3-ol.

[0198] Under nitrogen atmosphere at 0°C, DBU (20 mol%) was added to a solution of crude 1-benzhydryl-3-butylazetidine-3-ol (1.0 equiv., assumed to be 100% pure) and trichloroacetonitrile (4.0 equiv.) in anhydrous dichloromethane (0.4 M), and the mixture was slowly warmed to room temperature and stirred for 2 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the crude product was directly purified by silica gel column chromatography to obtain the desired compound ATA-17 (1.62 g, 37% yield) as a yellow oil with a purity of more than 90%.

[0199] 1 H NMR (500MHz, CDCl3): δ8.20(s,1H),7.47–7.42(m,4H),7.29(t,J=7.6Hz,4H),7.25–7.18(m,2H),4.43(s,1H ),3.53(d,J=9.5Hz,2H),3.17(d,J=9.5Hz,2H),2.36–2.12(m,2H),1.55–1.32(m,4H),0.95(t,J=7.1Hz,3H).

[0200] 13 C NMR (126MHz, CDCl3): δ159.7,142.3,128.5,127.6,127.3,91.8,79.7,78.2,63.4,33.4,25.7,23.0,14.2.

[0201] HRMS(ESI-TOF)m / z:calc'd for C22 H 26 Cl3N2O[M+H] + :439.1105; found439.1113.

[0202] Example 18 Preparation of ATA-18

[0203]

[0204] Under a nitrogen atmosphere, a solution of n-butyllithium (1.2 equiv.) in n-hexane was added dropwise to a solution of thiophene (12 mmol, 1.2 equiv.) in anhydrous tetrahydrofuran (0.5 M) and stirred at -78°C for 1 hour. Then, a solution of azetidine-3-one (1.0 equiv.) in tetrahydrofuran with a CHPh2 protective group was slowly added dropwise to the reaction mixture. The mixture continued to stir at -78°C for 10 minutes, then naturally returned to room temperature and reacted overnight. After the reaction was completed, a saturated aqueous solution of NH4Cl was added to quench the reaction. The aqueous layer was extracted 3 times with ethyl acetate, and the combined organic layers were then washed with brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain a crude product of 1-dibenzhydryl-3-(thiophene-2-yl)azetidine-3-ol.

[0205] Under nitrogen atmosphere at 0°C, DBU (20 mol%) was added to a solution of crude 1-benzhydryl-3-(thiophen-2-yl)azetidine-3-ol (1.0 equiv., assumed to be 100% pure) and trichloroacetonitrile (4.0 equiv.) in anhydrous dichloromethane (0.4 M), and the mixture was slowly warmed to room temperature and stirred for 2 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the crude product was directly purified by neutral alumina column chromatography to obtain the desired compound ATA-18 (2.13 g, 46% yield) as a white solid with a purity of more than 90%.

[0206] 1 H NMR (500MHz, CDCl3): δ8.29(s,1H),7.48–7.40(m,4H),7.29–7.23(m,6H),7.19–7.14(m,2 H), 6.99 (dd, J = 5.0, 3.7Hz, 1H), 4.47 (s, 1H), 3.86 (d, J = 9.5Hz, 2H), 3.49 (d, J = 9.3Hz, 2H).

[0207] 13 C NMR (126MHz, CDCl3): δ159.2,144.4,141.9,128.6,127.5,127.4,126.6,125.0,124.8,91.3,77.9,76.8,66.1.

[0208] HRMS(ESI-TOF)m / z:calc'd for C 22 H 20 Cl3N2OS[M+H] + :465.0356; found465.0362.

[0209] Example 19 Preparation of ATA-19

[0210]

[0211] Under a nitrogen atmosphere, a solution of n-butyl lithium (2.5 M, 1.2 equiv.) in n-hexane was added dropwise to a solution of benzofuran (10 mmol, 1.0 equiv.) in anhydrous tetrahydrofuran (0.5 M). The mixture was stirred at -78 ° C for 10 minutes, then naturally returned to room temperature and reacted for 2 hours. After cooling to -78 ° C again, a solution of azetidine-3-one (1.0 equiv.) in tetrahydrofuran with a CHPh2 protective group was slowly added dropwise to the reaction mixture. The mixture continued to stir at -78 ° C for 10 minutes, then naturally returned to room temperature and reacted overnight. After the reaction was completed, a saturated NH4Cl aqueous solution was added to quench the reaction. The aqueous layer was extracted 3 times with ethyl acetate, and the combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain a crude product of 1-dibenzyl-3-(benzofuran-2-yl)azetidine-3-ol.

[0212] Under nitrogen atmosphere at 0°C, DBU (20 mol%) was added to a solution of crude 1-benzhydryl-3-(benzofuran-2-yl)azetidine-3-ol (1.0 equiv., assumed to be 100% pure) and trichloroacetonitrile (4.0 equiv.) in anhydrous dichloromethane (0.4 M), and the mixture was slowly warmed to room temperature and stirred for 2 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the crude product was directly purified by silica gel column chromatography to obtain the desired compound ATA-19 (2.39 g, 48% yield) as a white solid with a purity of more than 90%.

[0213] 1 H NMR (500MHz, CDCl3): δ8.30(s,1H),7.60–7.55(m,1H),7.54–7.46(m,1H),7.46–7.41(m,4H),7.32–7.23(m ,6H),7.22–7.14(m,2H),6.92(d,J=1.2Hz,1H),4.52(s,1H),4.01(d,J=10.1Hz,2H),3.55(d,J=9.9Hz,2H).

[0214] 13 C NMR (126MHz, CDCl3): δ159.5,155.1,155.0,141.8,128.7,128.3,127.6,127.4,124.6,123.0,121.4,111.6,105.0,91.2,78.0,74.6,63.3.

[0215] HRMS(ESI-TOF)m / z:calc'd for C 26 H 21 Cl3N2NaO2[M+Na] + :521.0561; found521.0567.

[0216] Azetidination of nucleophiles

[0217] The equation for the following reaction is as follows:

[0218]

[0219] Wherein, R is a substituent group of phenyl.

[0220] The preparation process is as follows:

[0221] Step 1: To an oven-dried sealed tube (4 mL) were added azetidine trichloroacetimidate (0.1 mmol, 1.0 equiv.), Cu(OTf)2 (3.6 mg, 10 mol%), a nucleophile (0.2 mmol, 2.0 equiv.) and Molecular sieve (30mg, dried and activated under flame for 10 minutes before use). Anhydrous dichloromethane (1.0mL, 0.1M) was added with a syringe under a nitrogen atmosphere. After reacting for 12 hours at 35°C, the mixture was cooled to room temperature, the crude mixture was further diluted with dichloromethane, and then filtered through diatomaceous earth. The solvent was removed under reduced pressure using a rotary evaporator. The crude product was purified by preparative thin layer chromatography.

[0222] Step 2: To an oven-dried sealed tube (4 mL) were added azetidine trichloroacetimidate (0.1 mmol, 1.0 equiv.), MsOH (1.0 equiv.), a nucleophile (0.2 mmol, 2.0 equiv.) and Molecular sieve (30mg, dried and activated under flame for 10 minutes before use). Nitromethane (1.0mL, 0.1M) was added with a syringe under a nitrogen atmosphere. After reacting for 12 hours at 100°C, the mixture was cooled to room temperature, a small amount of potassium carbonate was added to the crude mixture to quench the reaction, and then filtered through diatomaceous earth. The solvent was removed under reduced pressure using a rotary evaporator. The crude product was purified by preparative thin layer chromatography.

[0223] During the preparation process, either step 1 or step 2 can be selected.

[0224] Example 20 Preparation of Compound 1

[0225]

[0226] According to step 1, the crude product was prepared from compound ATA-11 and 4-bromopyrazole, separated on a silica gel plate, and the developing solvent was petroleum ether: ethyl acetate = 20:1 (v / v), to obtain compound 1; the yield was 90%, the oil was in the form of an oil, and the purity was above 90%.

[0227] 1 H NMR (400MHz, CDCl3): δ7.54(s,1H),7.48–7.41(m,4H),7.40–7.31(m,4H),7.30–7.23 (m,6H),7.22–7.15(m,2H),4.55(s,1H),3.99(d,J=8.8Hz,2H),3.85(d,J=8.8Hz,2H).

[0228] 13 C NMR (101MHz, CDCl3): δ142.2,141.7,140.0,128.9,128.7,128.6,128.2,127.5,127.5,125.8,93.7,77.8,64.6,62.3.

[0229] HRMS(ESI-TOF)m / z:calc'd for C 25 H 23 BrN3[M+H] + :444.1070; found444.1077.

[0230] Example 21 Preparation of Compound 2

[0231]

[0232] According to step 1, the crude product was prepared from compound ATA-1 and 4-bromopyrazole, separated by silica gel plate, and the developing solvent was petroleum ether: ethyl acetate = 20:1 (v / v), to obtain compound 2; the yield was 95%, white solid, and the purity was above 90%.

[0233] 1 H NMR (500MHz, CDCl3): δ7.53(s,1H),7.47–7.40(m,4H),7.33–7.24(m,5H),7.21–7.13(m,4H) ,6.96–6.79(m,2H),4.55(s,1H),3.97(d,J=8.6Hz,2H),3.82(d,J=8.5Hz,2H),3.79(s,3H).

[0234] 13 C NMR (126MHz, CDCl3): δ159.4,141.8,140.0,134.1,128.7,128.5,127.5,127.4,127.3,114.2,93.5,77.8,64.7,62.0,55.4.

[0235] HRMS(ESI-TOF)m / z:calc'd for C 26 H 25 BrN3O[M+H] + :474.1176; found474.1171.

[0236] Example 22 Preparation of Compound 3

[0237]

[0238] According to step 1, the crude product was prepared from compound ATA-5 and 4-bromopyrazole, separated by silica gel plate, and the developing solvent was petroleum ether: ethyl acetate = 20:1 (v / v), to obtain compound 3; the yield was 86%, the oil was in the form of an oil, and the purity was above 90%.

[0239] 1 H NMR (500MHz, CDCl3): δ7.55(s,1H),7.48–7.41(m,4H),7.38(s,1H),7.32–7.23(m, 6H),7.24–7.17(m,4H),4.54(s,1H),3.95(d,J=8.7Hz,2H),3.82(d,J=8.7Hz,2H).

[0240] 13C NMR (126MHz, CDCl3): δ149.0,141.4,141.3,140.3,128.8,128.5,127.6,127.5,127.2,121.3,120.6(q,J=258.3Hz),94.1,77.9,64.7,61.7.

[0241] 19 F NMR (471 MHz, CDCl3): δ-57.80.

[0242] HRMS(ESI-TOF)m / z:calc'd for C 26 H 22 BrF3N3O[M+H] + :528.0893; found528.0888.

[0243] Example 23 Preparation of Compound 4

[0244]

[0245] According to step 1, the crude product was prepared from compound ATA-2 and 4-bromopyrazole, separated on a silica gel plate, and the developing solvent was petroleum ether: ethyl acetate = 20:1 (v / v) to obtain compound 4; the yield was 87%, white solid, and the purity was above 90%.

[0246] 1 H NMR (500MHz, CDCl3): δ7.53(s,1H),7.43(d,J=7.6Hz,4H),7.33(s,1H),7.30–7.23(m,4H),7. 24–7.16(m,4H),7.08–7.00(m,2H),4.53(s,1H),3.95(d,J=8.8Hz,2H),3.80(d,J=8.7Hz,2H).

[0247] 13 C NMR (126MHz, CDCl3): δ162.5 (d, J = 247.5Hz), 141.5, 140.2, 138.2 (d, J = 3.3Hz), 128.7, 128.5, 127.6 (d, J = 8.4Hz), 127.5, 127.5, 115.8 (d, J = 21.6Hz), 93.9, 77.8, 64.7, 61.8.

[0248] 19 F NMR (471MHz, CDCl3): δ-113.86.

[0249] HRMS(ESI-TOF)m / z:calc'd for C 25 H 22 BrFN3[M+H] + :462.0976; found462.0973.

[0250] Example 24 Preparation of Compound 5

[0251]

[0252] According to step 1, the crude product was prepared from compound ATA-12 and 4-bromopyrazole, separated by silica gel plate, and the developing solvent was petroleum ether: ethyl acetate = 20:1 (v / v), to obtain compound 5; the yield was 84%, white solid, and the purity was above 90%.

[0253] 1 H NMR (500MHz, CDCl3): δ7.57(s,1H),7.52–7.40(m,4H),7.34(s,1H),7.33–7.27(m,5H),7.24–7.19(m,3H),7.15–7.0 4(m,2H),4.59(s,1H),4.04(d,J=8.6Hz,2H),3.88(d,J=8.5Hz,2H),2.92(hept,J=6.9Hz,1H),1.26(d,J=7.0Hz,6H).

[0254] 13 C NMR (126MHz, CDCl3): δ149.6,142.0,141.8,139.9,128.8,128.7,128.6,127.6,127.5,126.3,124.1,123.4,93.5,77.7,64.5,62.5,34.2,24.1.

[0255] HRMS(ESI-TOF)m / z:calc'd for C 28 H 29 BrN3[M+H] + :486.1539; found486.1532.

[0256] Example 25 Preparation of Compound 6

[0257]

[0258] According to step 1, the crude product was prepared from compound ATA-8 and 4-bromopyrazole, separated on a silica gel plate, and the developing solvent was petroleum ether:ethyl acetate = 20:1 (v / v), to obtain compound 6; the yield was 72%, the oil was in the form of an oil, and the purity was above 90%.

[0259] 1 H NMR (500MHz, CDCl3): δ7.56(s,1H),7.52(s,1H),7.48–7.40(m,4H),7.32–7.24(m,7H),7 .23–7.12(m,3H),4.52(s,1H),4.13(d,J=9.4Hz,2H),3.80(d,J=9.4Hz,2H),1.92(s,3H).

[0260] 13 C NMR (126MHz, CDCl3): δ141.9,139.8,138.4,137.2,131.9,128.9,128.7,128.3,127.6,127.6,127.5,126.3,93.5,77.7,64.3,63.9,19.6.

[0261] HRMS(ESI-TOF)m / z:calc'd for C 26 H 25 BrN3[M+H] + :458.1226; found458.1239.

[0262] Example 26 Preparation of Compound 7

[0263]

[0264] According to the process of step 2, the crude product was prepared from compound ATA-9 and 4-bromopyrazole, separated by silica gel plate, and the developing solvent was petroleum ether: ethyl acetate = 4:1 (v / v), to obtain compound 7; the yield was 45%, white solid, and the purity was above 90%.

[0265] 1 H NMR (500MHz, CDCl3): δ8.64 (d, J=41.6Hz, 2H), 7.56 (s, 1H), 7.50–7.31 (m, 6H), 7.29 (t, J= 7.6Hz,5H),7.25–7.17(m,2H),4.54(s,1H),3.95(d,J=8.8Hz,2H),3.85(d,J=8.8Hz,2H).

[0266] 13C NMR (126MHz, CDCl3): δ149.4,147.2,141.3,140.5,133.2,128.8,128.5,127.7,127.5,94.4,77.9,64.5,60.6.

[0267] HRMS(ESI-TOF)m / z:calc'd for C 24 H 21 BrN4Na[M+Na] + :467.0842; found467.0839.

[0268] Example 27 Preparation of Compound 8

[0269]

[0270] According to the process of step 2, the crude product was prepared from compound ATA-11 and 3-phenyl-1-propylamine, separated by silica gel plate, and the developing solvent was petroleum ether: ethyl acetate = 4:1 (v / v), to obtain compound 8; the yield was 72%, the oil was in the form of an oil, and the purity was above 90%.

[0271] 1 H NMR (500MHz, CDCl3): δ7.49–7.41(m,4H),7.40–7.32(m,4H),7.31–7.27(m,5H),7.26–7.23(m,2H),7.22–7.16(m,3H),7.16–7.11(m, 2H), 4.41 (s, 1H), 3.45 (d, J = 8.4Hz, 2H), 3.35 (d, J = 8.2Hz, 2H), 2.64–2.57 (m, 2H), 2.38 (t, J = 7.0Hz, 2H), 1.75 (dq, J = 9.1, 7.0Hz, 2H).

[0272] 13 C NMR (126MHz, CDCl3): δ144.6,142.5,142.2,128.6,128.5,128.4,128.4,127.6,127.2,126.8,126.5,125.8,78.3,64.7,58.4,43.1,33.7,32.2.

[0273] HRMS(ESI-TOF)m / z:calc'd for C 31 H 33 N2[M+H] + :433.2638; found433.2639.

[0274] Example 28 Preparation of Compound 9

[0275]

[0276] According to the process of step 2, the crude product was prepared from compound ATA-6 and morpholine, separated by silica gel plate, and the developing solvent was petroleum ether: ethyl acetate = 9:1 (v / v), to obtain compound 9; the yield was 76%, the oil was in the form of an oil, and the purity was above 90%.

[0277] 1 H NMR (400MHz, CDCl3): δ7.53–7.45(m,2H),7.43–7.36(m,4H),7.30–7.22(m,4H),7.22–7.13(m,2H),7.11–7.0 3(m,2H),4.46(s,1H),3.67(t,J=4.6Hz,4H),3.50(d,J=8.2Hz,2H),3.43(d,J=8.2Hz,2H),2.31–2.24(m,4H).

[0278] 13 C NMR (101MHz, CDCl3): δ142.3,138.7,131.1,129.4,128.6,127.6,127.3,121.1,78.2,67.3,61.7,61.6,46.6.

[0279] HRMS(ESI-TOF)m / z:calc'd for C 26 H 28 BrN2O[M+H] + :463.1380; found463.1375.

[0280] Example 29 Preparation of Compound 10

[0281]

[0282] According to the process of step 2, the crude product was prepared from compound ATA-11 and 2-oxa-6-aza-spiro[3,3]heptane, separated by silica gel plate, and the developing solvent was petroleum ether:ethyl acetate = 4:1 (v / v), to obtain compound 10; the yield was 35%, the oil was in the form of an oil, and the purity was above 90%.

[0283] 1H NMR (500MHz, CDCl3): δ7.45–7.39(m,4H),7.35–7.29(m,2H),7.30–7.22(m,5H),7.22–7.15( m,4H),4.72(s,4H),4.39(s,1H),3.54(d,J=8.9Hz,2H),3.49(s,4H),3.28(d,J=8.9Hz,2H).

[0284] 13 C NMR (126MHz, CDCl3): δ142.5,128.6,128.3,127.5,127.3,127.1,127.0,126.6,81.7,77.7,60.5,59.2,57.7,37.9.

[0285] HRMS(ESI-TOF)m / z:calc'd for C 27 H 28 N2NaO[M+Na] + :419.2094; found419.2083.

[0286] Example 30 Preparation of Compound 11

[0287]

[0288] According to the process of step 2, the crude product was prepared from compound ATA-10 and morpholine, separated by silica gel plate, and the developing solvent was petroleum ether: ethyl acetate = 9:1 (v / v), to obtain compound 11; the yield was 35%, the oil was, and the purity was above 90%.

[0289] 1 H NMR (500MHz, CDCl3): δ7.63(d,J=8.0Hz,2H),7.44–7.35(m,4H),7.32(d,J=8.0Hz,2H),7.30–7.23(m,4H),7.22–7. 13(m,2H),4.47(s,1H),3.68(t,J=4.6Hz,4H),3.54(d,J=7.7Hz,2H),3.47(d,J=7.7Hz,2H),2.29(t,J=4.6Hz,4H).

[0290] 13C NMR (126MHz, CDCl3): δ143.6, 142.2, 129.4 (q, J = 32.4Hz), 128.6, 127.9, 127.6, 127.4, 125.0 (q, J = 3.8Hz), 124.3 (q, J = 272.2Hz), 78.2, 67.2, 62.0, 61.5, 46.6.

[0291] 19 F NMR (471 MHz, CDCl3): δ-62.40.

[0292] HRMS(ESI-TOF)m / z:calc'd for C 27 H 28 F3N2O[M+H] + :453.2148; found453.2146.

[0293] Example 31 Preparation of Compound 12

[0294]

[0295] According to the process of step 2, the crude product was prepared from compound ATA-11 and piperidine, separated by silica gel plate, and the developing solvent was petroleum ether: ethyl acetate = 9:1 (v / v), to obtain compound 12; the yield was 37%, the oil was in the form of an oil, and the purity was above 90%.

[0296] 1 H NMR (500MHz, CDCl3): δ7.43–7.37(m,4H),7.39–7.32(m,2H),7.32–7.25(m,1H),7.28–7.21(m,4H),7.20–7.13(m,4H ),4.53(s,1H),3.65(d,J=8.2Hz,2H),3.40(d,J=7.9Hz,2H),2.10(s,4H),1.52(p,J=5.6Hz,4H),1.29–1.21(m,2H).

[0297] 13 C NMR (126MHz, CDCl3): δ142.6,138.6,128.5,127.9,127.7,127.5,127.1,126.9,78.2,63.3,62.2,47.1,26.2,24.4.

[0298] HRMS(ESI-TOF)m / z:calc'd for C 27 H 31 N2[M+H] +:383.2482; found383.2488.

[0299] Example 32 Preparation of Compound 13

[0300]

[0301] According to step 1, the crude product was prepared from compound ATA-11 and aniline, separated by silica gel plate, and the developing solvent was petroleum ether: ethyl acetate = 20:1 (v / v), to obtain compound 13; the yield was 93%, the oil was in the form of an oil, and the purity was above 90%.

[0302] 1 H NMR (400MHz, CDCl3): δ7.86–7.78(m,2H),7.58–7.46(m,4H),7.41(dd,J=8.4,7.0Hz,2H),7.35–7.27(m,5H),7.26–7.16(m,2H),7.06 (dd,J=8.5,7.2Hz,2H),6.72–6.59(m,1H),6.38–6.27(m,2H),4.59(s,1H),4.49(s,1H),3.76(d,J=8.2Hz,2H),3.40(d,J=8.2Hz,2H).

[0303] 13 C NMR (101MHz, CDCl3): δ145.2,144.1,142.1,129.1,128.7,127.6,127.4,127.0,125.8,117.6,114.2,78.1,67.1,54.8.

[0304] HRMS(ESI-TOF)m / z:calc'd for C 28 H 27 N2[M+H] + :391.2169; found391.2182.

[0305] Example 33 Preparation of Compound 14

[0306]

[0307] According to step 1, the crude product was prepared from compound ATA-11 and 4-aminophenylboronic acid pinacol ester, separated by silica gel plate, and the developing solvent was petroleum ether: ethyl acetate = 9:1 (v / v), to obtain compound 14; the yield was 79%, the oil was in the form of an oil, and the purity was above 90%.

[0308] 1H NMR (400MHz, CDCl3): δ7.85–7.70(m,2H),7.56–7.44(m,6H),7.38(t,J=7.6Hz,2H),7.33–7.25(m,5H),7.24–7.13( m,2H),6.29(d,J=8.5Hz,2H),4.70(s,1H),4.57(s,1H),3.74(d,J=8.2Hz,2H),3.40(d,J=8.2Hz,2H),1.29(s,12H).

[0309] 13 C NMR (101MHz, CDCl3): δ147.8,143.7,142.0,136.2,128.7,127.6,127.4,127.0,125.8,113.4,83.3,78.0,67.0,54.8,24.9.

[0310] 11 B NMR (160 MHz, CDCl3): δ 31.18.

[0311] HRMS(ESI-TOF)m / z:calc'd for C 34 H 38 BN2O2[M+H] + :517.3021; ​​found517.3024.

[0312] Example 34 Preparation of Compound 15

[0313]

[0314] According to the process of step 2, the crude product was prepared from compound ATA-11 and 4-aminopyridine, separated by silica gel plate, and the developing solvent was dichloromethane: methanol = 20:1 (v / v), to obtain compound 15; the yield was 48%, the oil was, and the purity was above 90%.

[0315] 1 H NMR (500MHz, CDCl3): δ8.48 (s, 2H), 7.67 (d, J = 6.5Hz, 2H), 7.43 (dt, J = 8.2, 1.9Hz, 7H), 7.31 (t, J = 7. 5Hz,4H),7.26–7.18(m,4H),4.53(s,1H),3.89(d,J=8.2Hz,2H),3.82(d,J=8.4Hz,2H),2.78(s,1H).

[0316] 13C NMR (126MHz, CDCl3): δ159.7,140.7,139.9,139.0,129.8,129.5,129.0,128.0,127.4,125.6,111.4,77.7,65.8,64.6.

[0317] HRMS(ESI-TOF)m / z:calc'd for C 27 H 26 N3[M+H] + :392.2121; found392.2122.

[0318] Example 35 Preparation of Compound 16

[0319]

[0320] According to step 1, the crude product was prepared from compound ATA-11 and N-methylaniline, separated by silica gel plate, and the developing solvent was petroleum ether: ethyl acetate = 20:1 (v / v), to obtain compound 16; the yield was 84%, the oil was in the form of an oil, and the purity was above 90%.

[0321] 1 H NMR (500MHz, CDCl3): δ7.88–7.68(m,2H),7.54(d,J=7.6Hz,4H),7.44(t,J=7.6Hz,2H),7.32(t,J=7.8Hz,5H),7.22(t,J=7.2Hz,2H),7.1 4(t,J=7.8Hz,2H),6.69(t,J=7.3Hz,1H),6.39(d,J=8.1Hz,2H),4.51(s,1H),3.74(d,J=7.8Hz,2H),3.47(d,J=7.1Hz,2H),2.98(s,3H).

[0322] 13 C NMR (126MHz, CDCl3): δ147.3,143.9,142.2,129.0,128.8,128.7,127.5,127.4,127.2,126.1,116.5,113.2,78.4,66.4,60.3,35.4.

[0323] HRMS(ESI-TOF)m / z:calc'd for C 29 H 29 N2[M+H] + :405.2325; found405.2319.

[0324] Example 36 Preparation of Compound 17

[0325]

[0326] According to step 1, the crude product was prepared from compound ATA-11 and 6-bromoindazole, separated by silica gel plate, and the developing solvent was petroleum ether: ethyl acetate = 9:1 (v / v), to obtain compound 17; the yield was 93%, the oil was in the form of an oil, and the purity was above 90%.

[0327] 1 H NMR (500MHz, CDCl3): δ7.93(s,1H),7.84(s,1H),7.54–7.42(m,5H),7.39–7.32(m,2H),7.34 –7.25(m,5H),7.26–7.14(m,5H),4.57(s,1H),4.15(d,J=8.7Hz,2H),4.01(d,J=8.9Hz,2H).

[0328] 13 C NMR (126MHz, CDCl3): δ149.3,142.5,141.6,128.9,128.7,128.2,127.5,125.9,125.5,122.5,121.8,120.5,120.4,120.3,77.9,65.2,63.1.

[0329] HRMS(ESI-TOF)m / z:calc'd for C 29 H 25 BrN3[M+H] + :494.1226; found494.1228.

[0330] Example 37 Preparation of Compound 18

[0331]

[0332] According to the process of step 2, the crude product was prepared from compound ATA-11 and 6-chloro-1H-pyrazolo[3,4-B]pyridine, separated by silica gel plate, and the developing solvent was petroleum ether:ethyl acetate = 4:1 (v / v), to obtain compound 18; the yield was 33%, the oil was in the form of an oil, and the purity was above 90%.

[0333] 1H NMR (500MHz, CDCl3): δ7.89 (d, J = 8.7Hz, 1H), 7.72 (s, 1H), 7.46–7.42 (m, 4H), 7.40–7.31 (m, 5H), 7.29–7.22 (m,4H),7.21–7.16(m,2H),7.02(d,J=8.5Hz,1H),4.65(s,1H),4.29(d,J=8.9Hz,2H),4.00(d,J=9.0Hz,2H).

[0334] 13 C NMR (126MHz, CDCl3): δ157.0,152.3,141.7,141.2,132.3,129.0,128.7,128.6,127.6,127.5,126.4,122.5,119.4,112.7,77.6,64.7,64.1.

[0335] HRMS(ESI-TOF)m / z:calc'd for C 28 H 24 ClN4[M+H] + :451.1684; found451.1698.

[0336] Example 38 Preparation of Compound 19

[0337]

[0338] According to step 1, the crude product was prepared from compound ATA-11 and 2-phenylbenzimidazole, separated by silica gel plate, and the developing solvent was petroleum ether: ethyl acetate = 9:1 (v / v), to obtain compound 19; the yield was 92%, the oil was in the form of an oil, and the purity was above 90%.

[0339] 1 H NMR (500MHz, CDCl3): δ7.89 (d, J = 8.1Hz, 1H), 7.81–7.67 (m, 2H), 7.52–7.39 (m, 5H), 7.38–7.34 (m, 4H), 7.32–7. 28(m,2H),7.26–7.21(m,6H),7.18–7.09(m,3H),6.86(d,J=8.2Hz,1H),4.29(s,1H),3.81(s,2H),3.47(s,2H).

[0340] 13C NMR (126MHz, CDCl3): δ153.1,143.5,143.1,141.5,135.4,131.2,130.1,129.3,128.8,1 28.7,128.6,128.2,127.4,127.3,125.1,123.1,122.8,120.3,111.9,77.6,67.6,58.2.

[0341] HRMS(ESI-TOF)m / z:calc'd for C 35 H 30 N3[M+H] + :492.2434; found492.2438.

[0342] Example 39 Preparation of Compound 20

[0343]

[0344] According to step 1, the crude product was prepared from compound ATA-11 and 3-bromocarbazole, separated by silica gel plate, and the developing solvent was petroleum ether: ethyl acetate = 9:1 (v / v), to obtain compound 20; the yield was 77%, the oil was in the form of an oil, and the purity was above 90%.

[0345] 1 H NMR (400MHz, CDCl3): δ8.24(d,J=2.0Hz,1H),8.17–8.05(m,1H),7.54–7.48(m,4H),7.46–7.41(m,2H),7.35–7.25(m,8H), 7.29–7.18(m,4H),6.85(d,J=7.3Hz,1H),6.71(d,J=8.7Hz,1H),4.42(s,1H),4.25(d,J=7.8Hz,2H),3.98(d,J=7.8Hz,2H).

[0346] 13 C NMR (101MHz, CDCl3): δ142.9,141.7,139.9,138.2,129.0,128.9,128.5,127.9,127.6,127. 5,126.6,125.3,125.0,123.4,122.4,120.8,119.9,112.4,112.0,110.8,78.2,67.0,57.7.

[0347] HRMS(ESI-TOF)m / z:calc'd for C 34 H 28 BrN2[M+H]+ :543.1430; found543.1434.

[0348] Example 40 Preparation of Compound 21

[0349]

[0350] According to step 1, the crude product was prepared from compound ATA-11 and 1,2,3-benzotriazole, separated by silica gel plate, and the developing solvent was petroleum ether: ethyl acetate = 9:1 (v / v), to obtain compound 21; the yield was 42%, the oil was in the form of an oil, and the purity was above 90%.

[0351] 1 H NMR (500MHz, CDCl3): δ7.91–7.84(m,2H),7.47–7.37(m,6H),7.33–7.26(m,9H) ,7.22–7.18(m,2H),4.52(s,1H),4.43(d,J=9.3Hz,2H),4.05(d,J=9.3Hz,2H).

[0352] 13 C NMR (126MHz, CDCl3): δ144.4,141.7,141.6,128.8,128.7,128.2,127.6,127.5,126.6,125.6,118.5,78.1,66.6,64.6.

[0353] HRMS(ESI-TOF)m / z:calc'd for C 28 H 25 N4[M+H] + :417.2074; found417.2079.

[0354] Example 41 Preparation of Compound 22

[0355]

[0356] According to step 1, the crude product was prepared from compound ATA-11 and 5-phenyltetrazole, separated by silica gel plate, and the developing solvent was petroleum ether: ethyl acetate = 9:1 (v / v), to obtain compound 22; the yield was 78%, the oil was in the form of an oil, and the purity was above 90%.

[0357] 1H NMR (500MHz, CDCl3): δ8.24–8.01(m,2H),7.53–7.41(m,7H),7.39–7.28(m,9H) ,7.25–7.17(m,2H),4.54(s,1H),4.42(d,J=9.3Hz,2H),3.98(d,J=9.3Hz,2H).

[0358] 13 C NMR (126MHz, CDCl3): δ165.2,141.4,140.1,130.4,129.0,129.0,128.8,128.6,127.6,127.5,127.1,125.8,77.8,65.3,63.9.

[0359] HRMS(ESI-TOF)m / z:calc'd for C 29 H 26 N5[M+H] + :444.2183; found444.2188.

[0360] Example 42 Preparation of Compound 23

[0361]

[0362] According to the process of step 2, the crude product was prepared from compound ATA-11 and purine, separated by silica gel plate, and the developing solvent was petroleum ether: ethyl acetate = 2:1 (v / v), to obtain compound 23; the yield was 22%, the oil was, and the purity was above 90%.

[0363] 1 H NMR (500MHz, CDCl3): δ9.18(s,1H),8.88(s,1H),8.10(s,1H),7.48–7.44(m,4H),7.41–7.35(m,4H) ),7.34–7.27(m,5H),7.24–7.19(m,2H),4.55(s,1H),4.17(d,J=8.7Hz,2H),4.13(d,J=8.7Hz,2H).

[0364] 13 C NMR (126MHz, CDCl3): δ152.8,151.4,149.2,143.7,141.7,141.3,134.2,129.1,128.8,128.4,127.7,127.4,125.2,78.0,65.0,57.8.

[0365] HRMS(ESI-TOF)m / z:calc'd for C 27 H 24 N5[M+H] + :418.2026; found418.2031.

[0366] Example 43 Preparation of Compound 24

[0367]

[0368] According to step 1, the crude product was prepared from compound ATA-11 and 4-(trifluoromethoxy)benzenesulfonamide, separated by silica gel plate, and the developing solvent was petroleum ether: ethyl acetate = 4:1 (v / v), to obtain compound 24; the yield was 26%, yellow solid, and the purity was above 90%.

[0369] 1 H NMR (500MHz, CDCl3): δ7.41–7.31(m,6H),7.30–7.25(m,4H),7.23–7.16(m,2H),7.14–7.01(m, 5H),7.00–6.94(m,2H),5.76(s,1H),4.33(s,1H),3.66(d,J=9.0Hz,2H),3.49(d,J=9.0Hz,2H).

[0370] 13 C NMR (126MHz, CDCl3): δ151.4,141.6,139.9,139.5,129.1,128.7,128.2,127.7,127.5,127.4,120.5,120.3(q,J=259.6Hz),77.8,65.3,57.5.

[0371] 19 F NMR (471 MHz, CDCl3): δ-57.73.

[0372] HRMS(ESI-TOF)m / z:calc'd for C 29 H 26 F3N2O3S[M+H] + :539.1611; found539.1625.

[0373] Example 44 Preparation of Compound 25

[0374]

[0375] According to step 1, the crude product was prepared from compound ATA-11 and tert-butyl carbamate, separated on a silica gel plate, and the developing solvent was petroleum ether: ethyl acetate = 9:1 (v / v) to obtain compound 25; the yield was 24%, a white solid, and the purity was above 90%.

[0376] 1 H NMR (500MHz, CDCl3): δ7.64–7.58(m,2H),7.48–7.42(m,4H),7.38(t,J=7.7Hz,2H),7.31–7.24(m, 5H),7.21–7.14(m,2H),5.19(s,1H),4.52(s,1H),3.60(d,J=8.1Hz,2H),3.45(s,2H),1.38(s,9H).

[0377] 13 C NMR (126MHz, CDCl3): δ142.2,128.6,128.5,127.6,127.3,127.1,125.4,80.0,78.0,65.7,53.4,28.4.

[0378] HRMS(ESI-TOF)m / z:calc'd for C 27 H 31 N2O2[M+H] + :415.2380; found415.2382.

[0379] Example 45 Preparation of Compound 26

[0380]

[0381] According to step 1, the crude product was prepared from compound ATA-11 and dimethyl sulfoxide, separated on a silica gel plate, and the developing solvent was petroleum ether: ethyl acetate = 1:1 (v / v) to obtain compound 26; the yield was 46%, white solid, and the purity was above 90%.

[0382] 1 H NMR (500MHz, CDCl3): δ7.60–7.54(m,2H),7.44–7.34(m,6H),7.31–7.22(m,5H),7.20 –7.06(m,2H),4.48(s,1H),3.70(d,J=8.2Hz,2H),3.58(d,J=8.2Hz,2H),2.68(s,6H).

[0383] 13C NMR (126MHz, CDCl3): δ146.2,142.5,128.6,128.5,127.7,127.1,126.6,78.3,68.0,57.6,44.7.

[0384] HRMS(ESI-TOF)m / z:calc'd for C 24 H 26 N2NaOS[M+Na] + :413.1658; found413.1663.

[0385] Example 46 Preparation of Compound 27

[0386]

[0387] According to step 1, the crude product was prepared from compound ATA-11 and benzophenone imine, separated by silica gel plate, and the developing solvent was petroleum ether: ethyl acetate = 20:1 (v / v), to obtain compound 27; the yield was 88%, the oil was in the form of an oil, and the purity was above 90%.

[0388] 1 H NMR (500MHz, CDCl3): δ7.71–7.60(m,4H),7.45–7.33(m,9H),7.31–7.27(m,1H),7.26–7.19(m,5H) ,7.19–7.05(m,4H),6.91–6.73(m,2H),4.35(s,1H),3.39(d,J=6.3Hz,2H),3.20(d,J=6.3Hz,2H).

[0389] 13 C NMR (126MHz, CDCl3): δ166.9,147.7,142.7,140.6,137.7,130.2,128.8,128.7,1 28.4,128.4,128.1,128.1,127.9,127.5,127.0,126.5,125.9,78.0,68.4,61.9.

[0390] HRMS(ESI-TOF)m / z:calc'd for C 35 H 31 N2[M+H] + :479.2482; found479.2480.

[0391] Example 47 Preparation of Compound 28

[0392]

[0393] According to step 1, the crude product was prepared from compound ATA-11 and benzoic acid, separated by silica gel plate, and the developing solvent was petroleum ether: ethyl acetate = 9:1 (v / v), to obtain compound 28; the yield was 73%, white solid, and the purity was above 90%.

[0394] 1 H NMR (500MHz, CDCl3): δ8.11–8.02(m,2H),7.70–7.63(m,2H),7.62–7.55(m,1H),7.52–7.43(m,6H),7.40(t,J =7.7Hz,2H),7.35–7.25(m,5H),7.24–7.15(m,2H),4.52(s,1H),3.92(d,J=9.6Hz,2H),3.60(d,J=9.6Hz,2H).

[0395] 13 C NMR (126MHz, CDCl3): δ165.0,142.1,141.6,133.3,130.3,129.9,128.7,128.6,128.6,127.8,127.6,127.4,125.0,78.3,76.3,65.8.

[0396] HRMS(ESI-TOF)m / z:calc'd for C 29 H 26 NO2[M+H] + :420.1958; found420.1953.

[0397] Example 48 Preparation of Compound 29

[0398]

[0399] According to step 1, the crude product was prepared from compound ATA-11 and 1-phenylcyclopentanecarboxylic acid, separated by silica gel plate, and the developing solvent was petroleum ether: ethyl acetate = 20:1 (v / v), to obtain compound 29; the yield was 53%, the oil was in the form of an oil, and the purity was above 90%.

[0400] 1H NMR (500MHz, CDCl3): δ7.39–7.34(m,8H),7.31(dt,J=8.2,4.0Hz,1H),7.26–7.21(m,9H),7.18–7.12(m,2H),4.2 6(s,1H),3.68(d,J=9.6Hz,2H),3.15(d,J=9.6Hz,2H),2.84–2.53(m,2H),2.27–1.84(m,2H),1.83–1.62(m,4H).

[0401] 13 C NMR (126MHz, CDCl3): δ173.9,142.9,142.0,141.4,128.6,128.4,128.3,12 7.5,127.5,127.3,127.3,127.0,124.7,78.2,75.8,65.3,59.2,35.7,23.7.

[0402] HRMS(ESI-TOF)m / z:calc'd for C 34 H 34 NO2[M+H] + :488.2584; found488.2599.

[0403] Example 49 Preparation of Compound 30

[0404]

[0405] According to step 1, the crude product was prepared from compound ATA-11 and cedarwood, separated by silica gel plate, and the developing solvent was petroleum ether: ethyl acetate = 20:1 (v / v), to obtain compound 30; the yield was 54%, the oil was in the form of an oil, and the purity was above 90%.

[0406] 1H NMR (500MHz, CDCl3): δ7.68–7.60(m,2H),7.50–7.35(m,6H),7.32–7.20(m,5H),7.20–7.12(m,2 H),4.45(s,1H),3.72(dd,J=7.2,3.2Hz,1H),3.51(dd,J=6.8,3.3Hz,1H),3.33(d,J=6.9Hz,1H) ,3.26(d,J=7.3Hz,1H),1.87–1.75(m,3H),1.64(d,J=6.1Hz,1H),1.54–1.46(m,2H),1.44–1.34 (m,4H),1.30–1.19(m,5H),1.17–1.06(m,1H),1.02(s,3H),0.85(s,3H),0.75(d,J=7.2Hz,3H).

[0407] 13 C NMR (126MHz, CDCl3): δ146.9,142.7,142.6,128.5,128.5,128.1,127.6,127.6,127.1,127.1,126.8,126.6,81 .8,78.5,73.3,67.7,66.6,61.8,56.9,53.7,43.8,41.6,41.2,37.1,35.9,31.6,29.5,28.9,25.5,24.6,15.7.

[0408] HRMS(ESI-TOF)m / z:calc'd for C 37 H 46 NO[M+H] + :520.3574; found520.3574.

[0409] Example 50 Preparation of Compound 31

[0410]

[0411] According to step 1, the crude product was prepared from compound ATA-11 and phenol, separated by silica gel plate, and the developing solvent was petroleum ether: ethyl acetate = 20:1 (v / v), to obtain compound 31; the yield was 92%, the oil was in the form of an oil, and the purity was above 90%.

[0412] 1H NMR (400MHz, CDCl3): δ7.77–7.71(m,2H),7.55–7.47(m,4H),7.44–7.39(m,2H),7.35–7.28(m,5H),7.25–7.18(m,2H) ,7.17–7.08(m,2H),6.91–6.79(m,1H),6.71–6.47(m,2H),4.57(s,1H),3.80(d,J=8.9Hz,2H),3.51(d,J=8.9Hz,2H).

[0413] 13 C NMR (101MHz, CDCl3): δ155.2,142.4,142.2,129.3,128.7,128.7,127.5,127.4,127.4,125.1,120.8,116.5,78.1,75.5,66.2.

[0414] HRMS(ESI-TOF)m / z:calc'd for C 28 H 26 NO[M+H] + :392.2009; found392.2006.

[0415] Example 51 Preparation of Compound 32

[0416]

[0417] According to step 1, the crude product was prepared from compound ATA-11 and 2-mercaptobenzothiazole, separated by silica gel plate, and the developing solvent was petroleum ether: ethyl acetate = 9:1 (v / v), to obtain compound 32; the yield was 68%, white solid, and the purity was above 90%.

[0418] 1 H NMR (500MHz, CDCl3): δ7.97–7.94(m,1H),7.88–7.58(m,1H),7.44–7.37(m,3H),7.34–7.26(m,7H) ,7.25–7.19(m,5H),7.20–7.11(m,2H),4.43(s,1H),4.04(d,J=9.3Hz,2H),3.77(d,J=9.3Hz,2H).

[0419] 13C NMR (126MHz, CDCl3): δ162.9,153.6,143.1,141.9,136.7,128.6,128.4,1 27.5,127.5,127.3,127.0,126.2,125.0,122.7,121.1,77.5,65.5,51.9.

[0420] HRMS(ESI-TOF)m / z:calc'd for C 29 H 25 N2S2[M+H] + :465.1454; found465.1466.

[0421] Example 52 Preparation of Compound 33

[0422]

[0423] According to step 1, the crude product was prepared from compound ATA-11 and diphenylphosphine oxide, separated on a silica gel plate, and the developing solvent was petroleum ether:ethyl acetate = 1:1 (v / v), to obtain compound 33; the yield was 55%, the oil was in the form of an oil, and the purity was above 90%.

[0424] 1 H NMR (500MHz, CDCl3): δ7.77–7.65(m,4H),7.61–7.56(m,2H),7.52–7.44(m,2H),7.43–7.35(m,4H),7.33–7. 28(m,6H),7.25–7.19(m,5H),7.19–7.12(m,2H),4.41(s,1H),3.94(d,J=9.5Hz,2H),3.64(d,J=9.6Hz,2H).

[0425] 13 C NMR (126MHz, CDCl3): δ142.1, 142.0 (d, J = 3.2Hz), 133.9, 132.8, 131.9 (d, J = 3.2Hz), 131.6 (d, J = 10.6H z), 128.5, 128.4 (d, J = 1.8Hz), 128.0, 127.5, 127.2, 126.0, 78.3 (d, J = 8.3Hz), 77.7, 65.9 (d, J = 5.5Hz).

[0426] 31 P NMR (202 MHz, CDCl3): δ 29.20.

[0427] HRMS(ESI-TOF)m / z:calc'd for C34 H 31 NOP[M+H] + :500.2138; found500.2134.

[0428] Example 53 Preparation of Compound 34

[0429]

[0430] According to step 1, the crude product was prepared from compound ATA-11 and trimethylsilyl cyanide, separated on a silica gel plate, and the developing solvent was petroleum ether: ethyl acetate = 20:1 (v / v), to obtain compound 34; the yield was 31%, white solid, and the purity was above 90%.

[0431] 1 H NMR (500MHz, CDCl3): δ7.54–7.48(m,4H),7.47–7.38(m,4H),7.36–7.28(m,5H),7.27–7.20(m,2H), 4.69(s,1H),4.40(d,J=7.9Hz,1H),4.03–3.81(m,1H),3.53(t,J=6.9Hz,1H),3.48(t,J=7.6Hz,1H).

[0432] 13 C NMR (126MHz, CDCl3): δ140.7,140.1,137.5,128.9,128.9,128.9,128.1,128.1,128.0,128.0,127.8,127.5,116.5,75.1,58.1,57.4,38.4.

[0433] HRMS(ESI-TOF)m / z:calc'd for C 23 H 20 N2Na[M+Na] + :347.1519; found347.1529.

[0434] Example 54 Preparation of Compound 35

[0435]

[0436] According to step 1, the crude product was prepared from compound ATA-11 and N-methylindole, separated by silica gel plate, and the developing solvent was petroleum ether: ethyl acetate = 20:1 (v / v), to obtain compound 35; the yield was 67%, the oil was in the form of an oil, and the purity was above 90%.

[0437] 1H NMR (500MHz, CDCl3): δ7.67(d,J=7.9Hz,1H),7.54–7.44(m,6H),7.42–7.28(m,7H),7.26–7.16(m,4H), 7.09–7.02(m,1H),6.72(s,1H),4.56(s,1H),3.95(d,J=7.5Hz,2H),3.90(d,J=7.5Hz,2H),3.76(s,3H).

[0438] 13 C NMR (126MHz, CDCl3): δ148.0,142.7,137.6,128.6,128.3,127.6,127.2,126.8, 126.7,126.5,126.0,121.8,121.7,120.8,119.0,109.4,78.4,66.4,40.8,32.8.

[0439] HRMS(ESI-TOF)m / z:calc'd for C 31 H 29 N2[M+H] + :429.2325; found429.2344.

[0440] Example 55 Preparation of Compound 36

[0441]

[0442] According to step 1, the crude product was prepared from compound ATA-11 and allyl tributyltin, separated on a silica gel plate, and the developing solvent was petroleum ether: ethyl acetate = 20:1 (v / v), to obtain compound 36; the yield was 20%, the oil was in the form of an oil, and the purity was above 90%.

[0443] 1 H NMR (500MHz, CDCl3): δ7.44–7.39(m,4H),7.30–7.24(m,6H),7.22–7.13(m,3H),7.06–6.91(m,2H),5.75–5.5 8(m,1H),5.23–4.77(m,2H),4.35(s,1H),3.46(d,J=7.8Hz,2H),3.22(d,J=7.8Hz,2H),2.74(d,J=7.2Hz,2H).

[0444] 13C NMR (126MHz, CDCl3): δ147.5,142.7,134.8,128.5,128.2,127.6,127.1,126.1,125.9,117.4,77.9,63.1,46.3,41.6.

[0445] HRMS(ESI-TOF)m / z:calc'd for C 25 H 26 N[M+H] + :340.2060; found340.2070.

[0446] Example 56 Preparation of Compound 37

[0447]

[0448] According to step 1, the crude product was prepared from compound ATA-11 and tert-butyldimethyl(1-phenylvinyloxy)silane, separated by silica gel plate, and the developing solvent was petroleum ether:ethyl acetate = 20:1 (v / v) to obtain compound 37; the yield was 52%, white solid, and the purity was above 90%.

[0449] 1 H NMR (500MHz, CDCl3): δ7.98–7.78(m,2H),7.57–7.50(m,1H),7.44–7.39(m,2H),7.31–7.26(m,5H),7.26 –7.18(m,5H),7.19–7.10(m,5H),4.32(s,1H),3.70(s,2H),3.64(d,J=8.2Hz,2H),3.33(d,J=8.2Hz,2H).

[0450] 13 C NMR (126MHz, CDCl3): δ198.3,146.8,142.3,137.8,132.9,128.6,128.5,128.3,128.3,127.5,127.1,126.2,126.1,77.8,63.5,48.7,40.8.

[0451] HRMS(ESI-TOF)m / z:calc'd for C 30 H 28 NO[M+H] + :418.2165; found418.2159.

[0452] application

[0453] Embodiment 57

[0454]

[0455] To an oven-dried sealed tube (4 mL) were added ATA-15 (0.1 mmol, 1.0 equiv.), Cu(OTf)2 (3.6 mg, 10 mol%), 2-methylfuran (0.2 mmol, 2.0 equiv.) and Molecular sieves (30 mg, dried and activated under flame for 10 minutes before use). Anhydrous dichloromethane (1.0 mL, 0.1 M) was added by syringe under nitrogen atmosphere. After reacting at 35 ° C for 12 hours, the mixture was cooled to room temperature, the crude mixture was further diluted with dichloromethane, and then filtered through diatomaceous earth. The solvent was removed under reduced pressure using a rotary evaporator. The crude product was separated on a silica gel plate, and the developing solvent was petroleum ether: ethyl acetate = 9:1 (v / v) to obtain compound 38; the yield was 61%, white solid, and the purity was more than 90%.

[0456] Compound 38 (0.1 mmol, 1.0 equiv.) and NaIO4 (7.0 equiv.) were added to an oven-dried sealed tube (4 mL), and then n-heptane (0.6 mL), ethyl acetate (0.6 mL) and H2O (1.2 mL) were added in sequence using a syringe. The reaction mixture was stirred at room temperature for 10 minutes, and then RuCl3 (2.5 mol%) was added. After reacting at room temperature for 24 hours, deionized water was added to quench the reaction. The aqueous layer was extracted 3 times with ethyl acetate, and then the combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The crude product was separated on a silica gel plate, and the developing solvent was petroleum ether: ethyl acetate = 2:1 (v / v) to obtain compound 39; the yield was 53%, an oil, and the purity was more than 90%.

[0457] Compound 38:

[0458]

[0459] 1 H NMR (500MHz, CDCl3): δ7.35–7.27(m,2H),7.23–7.16(m,1H),7.13(dd,J=7.9,1.4Hz,1H),5.80(d,J=3.1Hz,1H) ,5.55(d,J=3.2Hz,1H),4.50(s,4H),2.50(hept,J=6.7Hz,1H),2.27(s,3H),1.47(s,9H),1.13(d,J=6.7Hz,6H).

[0460] 13C NMR (126MHz, CDCl3): δ156.5,156.3,151.7,147.7,139.3,127.9,127.2,1 27.2,125.7,107.3,106.1,79.7,61.3,60.3,42.3,29.7,28.6,24.4,13.8.

[0461] HRMS(ESI-TOF)m / z:calc'd for C 22 H 29 NNaO3[M+Na] + :378.2040; found378.2047.

[0462] Compound 39: (LPA1 receptor antagonist intermediate)

[0463]

[0464] 1 H NMR (400MHz, CDCl3): δ7.32–7.29(m,2H),7.22–7.18(m,1H),7.16–7.12(m,1H),4.61(d,J=8. 6Hz, 2H), 4.34 (d, J = 8.9Hz, 2H), 2.58 (hept, J = 6.7Hz, 1H), 1.43 (s, 9H), 1.16 (d, J = 6.7Hz, 6H).

[0465] 13 C NMR (101MHz, CDCl3): δ178.5,156.2,147.6,135.8,128.6,127.4,127.2,126.1,80.4,58.3,47.4,29.8,28.5,24.3.

[0466] HRMS(ESI-TOF)m / z:calc'd for C 18 H 26 NO4[M+H] + :320.1856; found320.1853.

[0467] Embodiment 58

[0468]

[0469] According to the method for synthesizing compound 39, ATA-14 (5 mmol) and 2-methylfuran (10 mmol, 2.0 equiv.) were used to prepare the compound in two steps. The crude product was separated on a silica gel plate with a developing solvent of petroleum ether:ethyl acetate = 1:1 (v / v) to obtain compound 40; the two-step yield was 41%, a white solid, and the purity was above 90%.

[0470] Compound 40 (1.6 mmol, 1.0 equiv.) was dissolved in 10 mL of dichloromethane, and ethanol (0.15 g, 2.0 equiv.), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.62 g, 2.0 equiv.) and 4-dimethylaminopyridine (39 mg, 0.2 equiv.) were added at 0°C. The reaction was stirred at room temperature overnight. After the reaction was completed, deionized water was added to quench the reaction. The aqueous layer was extracted 3 times with ethyl acetate, and then the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The crude product 41-int1 was obtained, which was pure enough to be directly used in the next step. A solution of crude 41-int1 (0.2 mmol, assumed purity is 100%, 1.0 equiv.) in dichloromethane (1.0 mL, 0.2 M) was added to an oven-dried sealed tube (4 mL). Trifluoroacetic acid (16.0 equiv.) was slowly added to the reaction mixture and stirred at room temperature for 3 hours. The solvent and excess trifluoroacetic acid were removed under reduced pressure to give the crude product 41-int2, which was used directly in the next step without purification. Acetic acid (15.0 equiv.) was added to a methanol solution (0.1 M) of crude 41-int2 (1.0 equiv.) and paraformaldehyde (10.0 equiv.). After the reaction mixture was stirred at 80 ° C for 16 hours, sodium cyanoborohydride (2.0 equiv.) was added and the reaction was stirred at room temperature for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure, and the crude product was separated on a silica gel plate with a developing solvent of petroleum ether:ethyl acetate = 4:1 (v / v) to obtain compound 41; the three-step yield was 45%, the product was an oil, and the purity was above 90%.

[0471] A solution of crude 41-int1 (0.2 mmol, assumed purity is 100%, 1.0 equiv.) in dichloromethane (1 mL, 0.2 M) was added to an oven-dried sealed tube (4 mL). Trifluoroacetic acid (16.0 equiv.) was slowly added to the reaction mixture and stirred at room temperature for 3 hours. The solvent and excess trifluoroacetic acid were removed under reduced pressure to give the crude product 41-int2, which was used directly in the next step without purification. 2,2-Diphenyl-4-bromobutyronitrile (2.0 equiv.) and potassium carbonate (3.0 equiv.) were added to a solution of crude 41-int2 (1.0 equiv.) in acetonitrile (0.1 M). The reaction mixture was sealed and stirred at 130 °C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered through celite, and the reaction solution was concentrated under reduced pressure. The crude product was separated on a silica gel plate with a developing solvent of petroleum ether:ethyl acetate = 4:1 (v / v) to obtain compound 42; the three-step yield was 59%, the product was an oil, and the purity was above 90%.

[0472] Compound 40 (high value-added product: 1300$ / g)

[0473]

[0474] 1 H NMR (400MHz, CDCl3): δ7.40–7.35(m,2H),7.34–7.27(m,3H),4.60(d,J=8.8Hz,2H),4.31(d,J=8.8Hz,2H),1.42(s,9H).

[0475] 13 C NMR (101MHz, CDCl3): δ178.0,156.2,139.3,128.9,128.0,126.6,80.4,58.0,47.2,28.5.

[0476] HRMS(ESI-TOF)m / z:calc'd for C 15 H 20 NO4[M+H] + :278.1387; found 278.1380.

[0477] Compound 41 (Pethidine azetidine analog)

[0478]

[0479] 1H NMR (500MHz, CDCl3): δ7.35–7.30(m,2H),7.29–7.22(m,3H),4.15(q,J=7.2Hz,2H) ,4.04(d,J=7.8Hz,2H),3.45(d,J=7.8Hz,2H),2.34(s,3H),1.20(t,J=7.2Hz,3H).

[0480] 13 C NMR (126MHz, CDCl3): δ174.2,140.8,128.6,127.2,126.3,65.4,61.5,48.9,46.0,14.1.

[0481] HRMS(ESI-TOF)m / z:calc'd for C 13 H 18 NO2[M+H] + :220.1332; found 220.1340.

[0482] Compound 42 (Lomotil azetidine analog)

[0483]

[0484] 1 H NMR (500MHz, CDCl3): δ7.39–7.30(m,9H),7.30–7.20(m,6H),4.13(q,J=7.1Hz,2H),4 .02(d,J=7.8Hz,2H),3.42(d,J=7.8Hz,2H),2.60–2.38(m,4H),1.18(t,J=7.2Hz,3H).

[0485] 13 C NMR (126MHz, CDCl3): δ174.0,140.5,139.9,129.0,128.6,128.1,127.3,126.8,126.2,122.1,63.5,61.5,55.8,49.8,49.0,37.0,14.0.

[0486] HRMS(ESI-TOF)m / z:calc'd for C 28 H 29 N2O2[M+H] + :425.2224; found425.2225.

[0487] The above embodiments are only used to help understand the method and core idea of ​​the present invention. It should be noted that, for those skilled in the art, several improvements and modifications can be made to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. An azetidine trichloroacetimidate, characterized in that It has the structure shown in formula I: wherein R is selected from substituted or unsubstituted alkyl, alkenyl, aryl or heteroaryl; PG is an amino protecting group.

2. The azetidine trichloroacetimidate according to claim 1, characterized in that R is a substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl, C6-C12 aryl or C4-C12 heteroaryl; The PG is selected from benzhydryl, benzyloxycarbonyl or tert-butyloxycarbonyl.

3. The azetidine trichloroacetimidate according to claim 2, characterized in that The R is a substituted or unsubstituted C1-C6 alkyl group, a C2-C6 alkenyl group, a monocyclic aromatic group, a condensed aromatic group of 2 to 3 aromatic groups, a monocyclic heteroaromatic group, or a condensed heteroaromatic group of 2 to 3 rings.

4. The azetidine trichloroacetimidate according to claim 3, characterized in that The R is a substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, vinyl, propenyl, butenyl, phenyl, naphthyl, pyridyl, benzofuranyl or thienyl.

5. The azetidine trichloroacetimidate according to any one of claims 1 to 4, characterized in that The substituent of R is selected from one or more of halogen, nitro, cyano, hydroxyl, amino, substituted or unsubstituted alkyl, alkoxy, acyl, aryl, heteroaryl, oxaborane group, and sulfonyl group.

6. The azetidine trichloroacetimidate according to claim 1, characterized in that The azetidine trichloroacetimidate has any of the following structures:

7. The method for preparing azetidine trichloroacetimidate according to any one of claims 1 to 6, characterized in that: The following steps are involved: S1) using RY and azetidin-3-one as raw materials, performing a nucleophilic addition reaction to obtain the azetidinol represented by formula Ⅰ-a; S2) reacting the azetidine alcohol represented by formula Ⅰ-a with trichloroacetonitrile to obtain the azetidine trichloroacetimidate represented by formula Ⅰ; Wherein, Y is halogen or hydrogen; R is selected from substituted or unsubstituted alkyl, alkenyl, aryl or heteroaryl; PG is an amino protecting group.

8. A method for preparing a functionalized 3,3-disubstituted azetidine compound, comprising the following steps: S1) using RY and azetidin-3-one as raw materials, performing a nucleophilic addition reaction to obtain the azetidinol represented by formula Ⅰ-a; S2) reacting the azetidine alcohol represented by formula Ⅰ-a with trichloroacetonitrile to obtain the azetidine trichloroacetimidate represented by formula Ⅰ; S3) reacting the azetidine trichloroacetimidate of formula I with a nucleophilic reagent to obtain a functionalized 3,3-disubstituted azetidine compound of formula II; Wherein, Y is halogen or hydrogen; R is a substituted or unsubstituted alkyl, alkenyl, aryl or heteroaryl group; PG is an amino protecting group; Nu is a nucleophile.

9. The preparation method according to claim 7 or 8, characterized in that: The nucleophilic addition reaction in step S1) is carried out under the action of an alkyl metal compound; The reaction in step S2) is carried out under the catalysis of a basic compound.

10. The preparation method according to claim 7 or 8, characterized in that: The reaction in step S3) is carried out under the activation of Lewis acid or Bronsted acid; The nucleophilic agent is a nucleophilic agent containing one or more of the elements C, N, O, S, and P.

Images