Preparation method of an azetidine compound

Abstract

The present invention relates to a method for preparing azetidine compounds. Using a copper(I) complex photosensitizer as a catalyst, it catalyzes the radical reaction of organic amines and alkynes to generate a series of azetidine compounds with a quaternary ring structure. Moreover, the preparation method is simple and the conditions are mild, solving the problems of harsh preparation conditions and narrow substrate scope in the prior art.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis, and particularly relates to a method for preparing azetidine compounds. Background Art

[0002] Azetidine is a four-membered saturated nitrogen heterocyclic compound widely used in medicinal chemistry. Due to its rigid chemical skeleton and novel chemical activity, it can be used as a synthetic building block for drug molecules. Although it is highly desirable to introduce azetidine into complex molecules, there is usually a lack of efficient and convenient synthetic methods to construct the nitrogen-containing four-membered ring skeleton. For example, the inherent ring strain and sterically crowded nature of the four-membered ring make it challenging to atom-economically prepare multi-substituted and multi-functionalized azetidines from simple starting materials. As shown in Reaction Scheme a, traditional azetidine synthesis methods include 4-exo-tet cyclization reactions with a narrow substrate scope. In recent years, a series of complex azetidine skeletons have been constructed through intramolecular and intermolecular photoinduced [2+2] aza-Paternò-Büchi reactions and radical ring expansion reactions of aziridines. Both methods require ultraviolet light and ultraviolet light photosensitizers, with relatively harsh conditions, strict requirements for the substituents of the substrates, and also suffer from the problem of narrow substrate scope. Moreover, the existing photocatalytic methods for generating four-membered rings mainly use precious metal iridium and ruthenium photosensitizers and can only be achieved under high-temperature conditions such as ultraviolet light, with high costs. Therefore, it is of great significance to develop new synthetic methods to obtain azetidine skeletons with different substituent structures and stereochemical structures.

[0003] Recently, a method for the efficient synthesis of allyl aromatics through photoinduced copper-catalyzed cross-coupling of tertiary amines with aromatic alkynes has been reported (as shown in reaction b). Cu(I)(Xantphos)(2,9-diisopropyl-1,10-phenanthroline)PF4 is used as a photosensitizer. Mechanistic studies have shown that the α-aminoalkyl intermediate adds to the alkyne, followed by 1,5-HAT of the vinyl group, and the final product allyl aromatic is obtained through homolytic cleavage of the C-N bond rather than azetidine. However, this method is limited to aryl alkynes and linear alkylamines. The photosensitive copper complex is cheaper and easier to prepare than other noble metal photosensitizers and exhibits unique catalytic properties in many important photoreactions. The continuous radical effect of the copper complex catalysis is due to its multiple accessible oxidation states and highly tunable redox properties. Currently, there is no literature reporting the preparation of a series of azetidine compounds using a photosensitive copper complex.

[0004] Summary of the Invention

[0005] The technical problem solved by the present invention is to provide a method for preparing azetidine compounds. Using a copper(I) complex photosensitizer as a catalyst, it catalyzes the radical reaction of organic amines with alkynes to generate a series of azetidine compounds with a four-membered ring structure. Moreover, the preparation method is simple and the conditions are mild, so as to solve the problems of harsh preparation conditions and narrow substrate scope in the prior art.

[0006] The specific solution provided by the present invention is as follows:

[0007] The present invention provides a method for preparing azetidine compounds. Under blue light irradiation, using a copper(I) complex photosensitizer as a photocatalyst, an organic amine and an alkyne are catalyzed to react to form an azetidine compound with a four-membered ring structure. The organic amine is selected from one of secondary amines or tertiary amines, and the copper(I) complex photosensitizer is selected from one of the following structures:

[0008]

[0009] Based on the technical solution of the present invention, the following beneficial effects are achieved:

[0010] (1) Based on the method of the present invention, under blue light irradiation, using a copper(I) complex photosensitizer as a catalyst, an organic amine and an alkyne undergo a radical reaction to form an azetidine compound with a four-membered ring structure. The substrate has a wide scope of application, and a series of azetidine compounds can be synthesized.

[0011] (2) The existing methods for generating four-membered rings by photocatalysis mainly use precious metal iridium and ruthenium photosensitizers, and the reaction can only be achieved under high heat conditions such as ultraviolet light. The copper photosensitizer used in the present invention is cheap and easily available, and the reaction conditions are mild. Under visible light blue light irradiation, an alkyl amine and an alkyne undergo a radical tandem cyclization reaction to construct a four-membered ring. The preparation method is simple and the conditions are mild, significantly reducing the production cost.

[0012] On the basis of the above solution, the present invention can also be improved as follows:

[0013] Further, the organic amine is a tertiary amine represented by formula I, and the structure of the azetidine compound is represented by formula III. The method for preparing the azetidine compound represented by formula III includes the following steps: Using the copper(I) complex photosensitizer as a photocatalyst, under blue light irradiation and under the protection of an inert gas, reacting the tertiary amine represented by formula I and the alkyne represented by formula II in a first organic solvent to form an azetidine compound with a four-membered ring structure represented by formula III. The first organic solvent is selected from one of acetonitrile, DMF, THF, 1,4-dioxane or a mixture of any proportion of several of them.

[0014]

[0015] The organic amine is a secondary amine represented by Formula IV, and the structure of the azetidine compound is as shown in Formula IV. The preparation of the azetidine compound shown in Formula IV comprises the following steps: using the copper(I) complex photosensitizer as a photocatalyst, under blue light irradiation and under the protection of an inert gas, reacting the secondary amine shown in Formula IV, the terminal alkyne shown in Formula II, and the aldehyde shown in Formula V in a second organic solvent to generate the azetidine compound with a four-membered ring structure shown in Formula VI. The second organic solvent is selected from one or a mixture of any proportions of acetonitrile, DMF, THF, and 1,4-dioxane,

[0016]

[0017] wherein, R 0 is selected from one of H, a substituted or unsubstituted alkyl group, and a substituted or unsubstituted aromatic group, and R 1 is selected from one of a substituted or unsubstituted alkyl group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, a substituted or unsubstituted silyl group, and a substituted or unsubstituted ester group; R 2 is selected from one of H and a substituted or unsubstituted alkyl group, R 3 is selected from a substituted or unsubstituted alkyl group, R 4 and R 8 are each independently selected from one of H, a substituted or unsubstituted alkyl group, and a substituted or unsubstituted aromatic group and R 4 and R 8 are not simultaneously H, or R 4 and R 8 combine to form a cyclic group, R 5 and R 6 are each independently selected from an alkyl group or combine to form a cyclic group, and R 7 is selected from one of an alkyl group and an aromatic group.

[0018] Based on the method of the present invention, the Cu photosensitizer catalyzes the radical tandem reaction of a tertiary amine (having at least one α-tertiary carbon) with alkynes having different substituents, involving the functionalization reaction of two C(sp 3 )-H bonds at the α-position of the nitrogen atom to construct an azetidine skeleton, and successfully extends this strategy to the three-component (secondary amine, aldehyde, alkyne) radical tandem cyclization reaction. The use of different aldehydes and secondary amines further broadens the scope of substrate application, providing a new intermolecular cyclization strategy and successfully constructing polysubstituted azetidine compounds; the wide source of raw materials, visible light, inexpensive and easily available photocatalyst, and mild reaction conditions make this reaction more suitable for industry.

[0019] Preferably, R 0 is selected from one of a methyl group, a phenyl group, and a chlorophenyl group;

[0020] Preferably, R 1 is selected from one of substituted or unsubstituted phenyl, substituted or unsubstituted 2-pyridyl, substituted or unsubstituted formate group, and substituted or unsubstituted trimethylsilyl;

[0021] Preferably, when R 1 is substituted phenyl, substituted 2-pyridyl, substituted formate group, or substituted trimethylsilyl, the substituent is selected from one of trifluoromethyl, nitrile group, sulfonamide group, amide group, alkoxy group, alkyl group, or halogen.

[0022] Preferably, R 2 is selected from H or methyl;

[0023] Preferably, R 3 is selected from one of methyl, ethyl, isopropyl, and cyclohexyl;

[0024] Preferably, the R 5 is H, and R 4 is selected from one of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, and substituted or unsubstituted isopropyl. When the R 4 is substituted methyl, the substituent is selected from one of ester group, phenyl, or 2-furyl;

[0025] Preferably, the R 5 and R 6 are respectively methyl, or the R 5 and R 6 combine to form cyclohexane;

[0026] Preferably, R 7 is isopropyl.

[0027] Preferably, Formula III is selected from one of the following structures:

[0028]

[0029] Among them, R is selected from one of H, 4-trifluoromethyl, 4-nitrile group, 2-nitrile group, 4-sulfonamide group, 4-amide group, 4-methoxy, 4-tert-butyl, 4-methyl, 4-bromo, 3-chloro, 2-fluoro, or 4-fluoro.

[0030] By using the method of the present invention to prepare the azetidine compound with the above structure, the product yield can reach more than 50%, and the diastereoselectivity is high.

[0031] Preferably, Formula IV is selected from one of the following structures:

[0032]

[0033] By using the method of the present invention to prepare the azetidine compound with the above structure, the product yield can reach more than 50%, and the diastereoselectivity is high.

[0034] Furthermore, the molar ratio of the tertiary amine shown in Formula I, the terminal alkyne shown in Formula II, and the copper(I) complex photosensitizer is (1-3):1:(2%-8%), and the yield of the azetidine compound with a four-membered ring structure shown in Formula III is high.

[0035] Furthermore, the molar ratio of the secondary amine shown in Formula IV, the terminal alkyne shown in Formula II, the aldehyde shown in Formula V, and the copper(I) complex photosensitizer is (1-3):1::(1-3):(2%-8%), and the yield of the azetidine compound with a four-membered ring structure shown in Formula VI is high.

[0036] Furthermore, the tertiary amine shown in Formula I and the terminal alkyne shown in Formula II are reacted in a first organic solvent for 6-24 h and then filtered, and the filtrate is concentrated and subjected to column chromatography to obtain the azetidine compound with a four-membered ring structure shown in Formula III.

[0037] Furthermore, in the preparation of the azetidine compound with a four-membered ring structure shown in Formula III, the eluent used for column chromatography is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate in the mixed solution is 1:1-10:1.

[0038] Furthermore, the secondary amine shown in Formula IV, the terminal alkyne shown in Formula II, and the aldehyde shown in Formula V are reacted in a second organic solvent for 6-24 h and then filtered, and the filtrate is concentrated and subjected to column chromatography to obtain the azetidine compound with a four-membered ring structure shown in Formula VI.

[0039] Preferably, in the preparation of the azetidine compound with a four-membered ring structure shown in Formula VI, the eluent used for column chromatography is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate in the mixed solution is 1:1-10:1.

[0040] The additional aspects and advantages of the present invention will be partially given in the following description, partially become apparent from the following description, or be understood through the practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 It is a mechanism diagram based on the preparation process of the compound in Example 1 of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0042] The embodiments of the present invention will be described in detail below. The following described embodiments are exemplary and are intended to explain the present invention and should not be construed as limiting the present invention.

[0043] The specific solutions provided by the present invention include the following steps:

[0044] Example 1

[0045] The preparation method of compound III-1 (3-benzyl-1-isopropyl-2,2,4-trimethylazetidine) is as follows:

[0046]

[0047] As shown in Reaction Scheme A, under nitrogen protection and at room temperature, copper complex [(DPEphos)(bcp)Cu]PF6 (0.010 mmol, 5 mol%) (PS4), the alkylamine shown in Formula I-1 (0.4 mmol, 2.0 equiv), and the alkyne shown in Formula II (0.2 mmol, 1 equiv, where R 1 is phenyl and R 2 is H) were added to a 3 ml reaction flask, dissolved in 1 ml of anhydrous acetonitrile, the bottle cap was covered, sealed with a sealing film, and then placed under a Blue LED for reaction for 24 h. After the reaction was completed, it was filtered through diatomaceous earth. The filtrate was concentrated and then separated by column chromatography to obtain the final product III-1. The product yield was 93%, and the dr value was greater than 20:1.

[0048]

[0049] Structure characterization data of the product: 1 H NMR (CDCl3, 400 MHz) δ 7.27 - 7.23 (m, 2H), 7.18 - 7.14 (m, 3H), 2.85 - 2.81 (m, 2H), 2.76 - 2.70 (m, 1H), 2.66 (dd, J = 16.0, 8.0 Hz, 1H), 2.57 (dd, J = 16.0, 8.0 Hz, 1H), 1.95 (q, J = 8.0 Hz, 1H), 1.20 (s, 3H), 1.16 (s, 3H), 0.96 - 0.92 (m, 9H). 13 C NMR (CDCl3, 100 MHz): δ 140.6, 128.8, 128.4, 125.9, 62.5, 61.3, 50.9, 50.1, 34.6, 32.9, 23.7, 23.4, 22.0, 15.8. IR (neat) cm -1 3027, 2964, 2922, 2868, 2814, 1603, 1495, 1453, 1380, 1362, 1327, 1297, 1269, 1238, 1213, 1191, 1150, 1073, 1030, 959, 937, 908, 763, 738, 697. HRMS (ESI+): C16 H 26 N[M + H] + :calcd: 232.2060, found: 232.2061.

[0050] Example 2

[0051] The preparation method of compound III - 2 (2 - ((1 - isopropyl - 2,2,4 - trimethylazetidin - 3 - yl)methyl)pyridine) is as follows:

[0052] Under argon protection, at room temperature, copper complex PS3 (0.004 mmol, 2 mol%), the alkylamine shown in formula I - 1 (0.6 mmol, 3 equiv), and the alkyne shown in formula II (0.2 mmol, 1 equiv, where R 1 is 2 - pyridyl, R 2 is H) were added to a 25 - ml reaction flask, dissolved in 15 ml of DMF, the bottle cap was covered, sealed with a sealing film, and then placed under a Blue LED for reaction for 6 h. After the reaction was completed, it was filtered through diatomaceous earth. The filtrate was concentrated and then separated by column chromatography to obtain the final product III - 1. The product yield was 80%, and the dr value was greater than 20:1.

[0053] Structure characterization data of the product: 1 H NMR(CDCl3, 400 MHz)δ8.49(d, J = 8.0 Hz, 1H), 7.55(t, J = 8.0 Hz, 1H), 7.13 - 7.05(m, 2H), 2.91 - 2.68(m, 4H), 2.07(q, J = 8.0 Hz, 1H), 1.18(s, 3H), 1.17(s, 3H), 0.93 - 0.90(m, 9H). 13 C NMR(CDCl3, 100 MHz):δ160.6, 149.3, 136.3, 123.1, 121.2, 62.5, 61.0, 50.1, 49.8, 37.3, 32.7, 23.6, 23.3, 21.9, 16.0. IR(neat) cm -1 2962, 2921, 2868, 2820, 1589, 1568, 1471, 1434, 1380, 1362, 1328, 1302, 1272, 1238, 1209, 1189, 1149, 1100, 1076, 1049, 993, 961, 934, 748, 719. HRMS(ESI+): C 15 H 25N2[M+H] + :calcd:233.2012,found:233.2017.

[0054] Example 3

[0055] The preparation method of compound III-3 (ethyl 1-isopropyl-2,2,4-trimethylazetidin-3-yl)acetate) is as follows:

[0056]

[0057] Under nitrogen protection and at room temperature, copper complex PS5 (0.016 mmol, 8 mol%), the alkylamine shown in formula I-1 (0.2 mmol, 1 equiv), and the alkyne shown in formula II (0.2 mmol, 1 equiv, where R 1 is ethyl formate group, R 2 is H) were added to a 50 ml reaction flask, 30 ml of THF was added for dissolution, the bottle cap was covered, sealed with a sealing film, and then placed under a Blue LED for reaction for 12 h. After the reaction was completed, it was filtered through diatomaceous earth. After the filtrate was concentrated, it was separated by column chromatography to obtain the final product III-1. The product yield was 82%, and the dr value was greater than 20:1.

[0058] Structure characterization data of the product: 1 H NMR(CDCl3,400MHz)δ4.12(q,J=8.0Hz,2H),2.79-2.67(m,2H),1.99(q,J=8.0Hz,1H),2.31(dt,J=16.0,8.0Hz,2H),2.04(q,J=8.0Hz,1H),1.29-1.21(m,9H),1.10(s,3H),0.96-0.94(m,6H). 13 C NMR(CDCl3,100MHz):δ172.8,62.2,60.6,60.5,50.2,45.4,33.6,32.6,23.4,23.3,21.9,15.6,14.3.IR(neat)cm -1 2965,2927,2871,2819,1734,1463,1416,1375,1303,1246,1182,1145,1097,1031,961,938,855,718.HRMS(ESI+):C 13 H 26 NO2[M+H] +: calcd: 228.1958, found: 228.1962.

[0059] Example 4

[0060] The preparation method of compound III-4 (1-isopropyl-2,2,4-trimethyl-3-((trimethylsilyl)methyl)azetidine) is as follows:

[0061] Under nitrogen protection, at room temperature, copper complex PS6 (0.010 mmol, 5 mol%), the alkylamine shown in formula I-1 (0.5 mmol, 2.0 equiv), and the alkyne shown in formula II (0.2 mmol, 1 equiv, where R 1 is trimethylsilyl and R 2 is H) were added to a 3 ml reaction flask, dissolved in 1,4-dioxane, the bottle cap was covered, sealed with a sealing film, and then placed under a Blue LED for reaction for 16 h. After the reaction was completed, it was filtered through diatomaceous earth. The filtrate was concentrated and then separated by column chromatography to obtain the final product III-1. The product yield was 85%, and the dr value was greater than 20:1.

[0062] Structure characterization data of the product: 1 H NMR (CDCl3, 400 MHz) δ 2.71 - 2.61 (m, 2H), 1.67 (q, J = 8.0 Hz, 1H), 1.21 (s, 6H), 1.03 - 0.92 (m, 9H), 0.51 (m, 2H), 0.00 (s, 9H). 13 C NMR (CDCl3, 100 MHz): δ 63.1, 50.1, 45.9, 32.4, 23.5, 23.4, 22.6, 22.0, 15.8, 15.3, 0.6. IR (neat) cm -1 2962, 2927, 2905, 2869, 2821, 1381, 1360, 1322, 1249, 1199, 1146, 1100, 1019, 911, 859, 834, 806, 756, 723. HRMS (ESI+): C 13 H 30 NSi [M + H] + : calcd: 228.2142, found: 228.2148.

[0063] Example 5

[0064] The preparation method of compound III-5 (3-benzyl-1-isopropyl-2,2,3,4-tetramethylazetidine) is as follows:

[0065]

[0066] Same as Example 1, except that R 1 is phenyl and R 2 is methyl. The product yield is 72%, and the dr value is greater than 20:1.

[0067] Structure characterization data of the product: 1 H NMR(CDCl3,400MHz)δ7.26-7.17(m,3H),7.10(d,J=8.0Hz,2H),3.23(q,J=8.0Hz,1H),2.84-2.76(m,2H),2.38(d,J=12.0Hz,1H),1.30(s,3H),1.14(s,3H),0.97-0.94(m,9H),0.78(d,J=8.0Hz,3H). 13 C NMR(CDCl3,100MHz):δ139.5,130.1,128.0,126.0,65.1,63.5,50.0,42.1,26.9,23.9,22.7,18.1,17.8,17.1.IR(neat)cm -1 3062,3027,2963,2087,2815,1602,1494,1453,1380,1328,1262,1227,1186,1154,1120,1077,1016,968,909,872,803,759,702.HRMS(ESI+):C 17 H 28 N[M+H] + :calcd:246.2216,found:246.2216.

[0068] Example 6: Compound III-6

[0069] (methyl 4-((1-isopropyl-2,2,3,4-tetramethylazetidin-3-yl)methyl)benzoate) The preparation method is as follows:

[0070]

[0071] Same as Example 1, except that R 1is methyl 4-formylphenyl, and R 2 is methyl. The yield of the final product was 85%, and the dr value was greater than 20:1.

[0072] Structure characterization data of the product: 1 H NMR(CDCl3,400MHz)δ7.92(d,J=8.0Hz,2H),7.18(d,J=8.0Hz,2H),3.90(s,3H),3.25(q,J=8.0Hz,1H),2.88(d,J=12.0Hz,1H),2.83 - 2.77(m,1H),2.43(d,J=12.0Hz,1H),1.30(s,3H),1.14(s,3H),0.97 - 0.94(m,9H),0.76(d,J=8.0Hz,3H). 13 C NMR(CDCl3,100MHz):δ167.3,145.2,130.1,129.3,128.0,65.2,63.4,52.1,50.0,42.1,42.1,26.8,23.8,22.6,18.1,17.8,17.1.IR(neat)cm -1 2964,2932,2817,1722,1610,1453,1414,1380,1327,1227,1180,1154,1109,968,865,839,815,770,714.HRMS(ESI+):C 19 H 30 NO2[M + H] + :calcd:304.2271,found:304.2274.

[0073] Example 7

[0074] The preparation method of compound III - 7(ethyl 2-(1-isopropyl-2,2,3,4-tetramethylazetidin-3-yl)acetate(4t)) is as follows:

[0075]

[0076] Same as Example 1, except that R 1 is ethyl 4-formylphenyl, and R 2 is methyl. The yield of the final product was 88%, and the dr value was greater than 20:1.

[0077] Structure characterization data of the product: 11H NMR (CDCl3, 400 MHz) δ 4.08 (q, J = 8.0 Hz, 2H), 3.01 - 2.96 (m, 1H), 2.75 - 2.69 (m, 1H), 2.35 - 2.22 (m, 2H), 1.25 - 1.11 (m, 11H), 1.05 - 0.91 (m, 10H). 13 13C NMR (CDCl3, 100 MHz): δ 172.4, 64.7, 63.3, 60.2, 49.9, 41.3, 40.1, 26.8, 23.8, 22.6, 17.5, 17.3, 16.7, 14.4. IR (neat) cm -1 2965, 2873, 2819, 1733, 1452, 1368, 1329, 1277, 1224, 1179, 1156, 1116, 1070, 1033, 971, 948, 919, 870, 796, 730, 702. HRMS (ESI+): C 14 H 28 NO2[M + H] + : calcd: 242.2115, found: 242.2123.

[0078] Example 8

[0079] Compound III - 8

[0080] ((8R,9S,13S,14S)-3-((1-isopropyl-2,2,4-trimethylazetidin-3-yl)methyl)-13-methyl-7,8,9,11,12,13,15,16-octahydro-6H-cyclopenta[a]phenanthren-17(14H)-one (4) was prepared as follows:

[0081]

[0082] Same as Example 1, except that R 1 is The final product was obtained with a yield of 75% and a dr value greater than 20:1.

[0083] Structure characterization data of the product: 11H NMR (CDCl3, 400 MHz) δ 7.17 (d, J = 8.0 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.89 (s, 1H), 2.88 - 2.82 (m, 2H), 2.74 - 2.71 (m, 1H), 2.62 - 2.24 (m, 5H), 2.18 - 1.94 (m, 6H), 1.67 - 1.40 (m, 6H), 1.20 (s, 3H), 1.15 (s, 3H), 1.01 - 0.90 (m, 12H). 13 13C NMR (CDCl3, 100 MHz): δ 221.2, 138.0, 137.2, 136.3, 129.4, 126.2, 125.3, 62.6, 61.4, 50.6, 50.1, 48.1, 44.4, 44.3, 38.3, 36.0, 34.1, 33.0, 31.7, 29.5, 26.7, 25.8, 23.9, 23.4, 22.0, 21.7, 15.9, 14.0. IR (neat) cm- 1 2961, 2926, 2865, 1738, 1499, 1453, 1437, 1405, 1374, 1327, 1257, 1212, 1188, 1149, 1115, 1082, 1052, 1006, 962, 908, 820, 782, 729. HRMS (ESI+): C 28 H 42 NO[M + H] + : calcd: 408.3261, found: 408.3266.

[0084] Example 9: Compound III - 9

[0085] ((3S,8S,9S,10R,13R,14S,17R)-10,13 - dimethyl - 17 - ((R)-6 - methylheptan - 2 - yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17 - tetradecahydro - 1H - cyclopenta[a]phenanthren - 3 - yl - 2 - (1 - isopropyl - 2,2,4 - trimethylazetidin - 3 - yl)acetate)

[0086] The preparation method is as follows

[0087] Same as Example 1, except that R 1 is The final product yield was 83%, and the dr value was greater than 20:1.

[0088] Structural characterization data of the product: 1 H NMR(CDCl3,400MHz)δ5.37(d,J=4.0Hz,1H),4.63-4.55(m,1H),2.77-2.67(m,2H),2.35-2.25(m,4H),2.08-1.84(m,7H),1.56-0.85(m,47H),0.67(s,3H). 13 C NMR(CDCl3,100MHz):δ172.2,139.7,122.9,74.2,60.8,56.8,56.3,50.2,50.2,45.5,42.4,39.9,39.7,38.3,37.1,36.7,36.3,35.9,34.0,32.6,32.0,32.0,28.4,28.2,27.9,24.4,24.0,23.4,23.3,23.0,22.7,21.9,21.2,19.5,18.9,15.7,12.0.IR(neat)cm- 1 2957,2932,2868,2824,1724,1464,1439,1377,1327,1296,1252,1189,1135,1105,1067,1030,1009,959,940,909,874,842,800,732,699.HRMS(ESI+):C 38 H 66 NO2[M+H] + :calcd:568.5088,found:568.5089.

[0089] Example 10

[0090] Compound III-10

[0091] (N-(3-((1-isopropyl-2,2,4-trimethylazetidin-3-yl)methyl)phenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine) was prepared as follows:

[0092]

[0093] Same as Example 1, except that R 1 is The final product yield was 87%, and the dr value was greater than 20:1.

[0094] Structural characterization data of the product: 1 H NMR (CDCl3, 400 MHz) δ 8.64 (s, 1H), 7.57 - 7.45 (m, 3H), 7.3 - 7.22 (m, 3H), 6.96 (d, J = 8.0 Hz, 1H), 4.28 - 4.23 (m, 4H), 3.83 - 3.80 (m, 4H), 3.44 (s, 6H), 2.92 - 2.86 (m, 1H), 2.78 - 2.67 (m, 2H), 2.60 (dd, J = 12.0, 8.0 Hz, 1H), 2.02 (q, J = 8.0 Hz, 1H), 1.24 (s, 3H), 1.19 (s, 3H), 1.03 - 0.94 (m, 9H). 13 C NMR (CDCl3, 100 MHz): δ 156.6, 154.5, 153.9, 148.8, 147.6, 141.5, 138.8, 129.0, 124.7, 122.3, 119.5, 109.3, 108.9, 102.8, 71.0, 70.5, 69.3, 68.4, 63.1, 61.4, 59.4, 59.4, 50.7, 50.2, 34.7, 32.7, 23.6, 23.2, 21.8, 16.0. IR (neat) cm -1 2962, 2924, 2821, 1620, 1576, 1530, 1433, 1389, 1330, 1254, 1205, 1147, 1125, 1097, 1069, 1030, 910, 852, 783, 729, 696. HRMS (ESI+): C 30 H 43 N4O4 [M + H] + : calcd: 523.3279, found: 523.3282.

[0095] Example 11

[0096] The preparation method of compound III - 11 (methyl 4 - ((1 - isopropyl - 2,2 - dimethylazetidin - 3 - yl)methyl)benzoate) is as follows:

[0097]

[0098] As shown in Reaction Scheme B, under the protection of an inert gas and at room temperature, the copper complex [(DPEphos)(bcp)Cu]PF6 (0.010 mmol, 5 mol%) (PS4), the alkylamine shown in Formula I (0.4 mmol, 2.0 equiv, where R 0 is H, R 3 is isopropyl, R 5 and R 6 are methyl) and the alkyne shown in Formula II-1 (0.2 mmol, 1 equiv, where R 1 is 4-(methoxycarbonyl)phenyl) were added to a 3 mL reaction flask, dissolved in anhydrous acetonitrile, capped, sealed with parafilm, and then placed under a Blue LED for reaction for 24 h. After the reaction was completed, it was filtered through diatomaceous earth. The filtrate was concentrated and then separated by column chromatography to obtain the final product III-1 with a yield of 78% and a dr value greater than 20:1.

[0099]

[0100] Structure characterization data of the product: 1 H NMR (CDCl3, 400 MHz) δ 7.93 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 3.89 (s, 3H), 3.21 (t, J = 8.0 Hz, 1H), 2.81 - 2.73 (m, 1H), 2.69 (t, J = 8.0 Hz, 1H), 2.62 - 2.56 (m, 1H), 1.22 (s, 3H), 1.17 (s, 3H), 0.90 (dd, J = 16.0, 8.0 Hz, 6H). 13 C NMR (CDCl3, 100 MHz): δ 167.2, 146.3, 129.8, 128.6, 128.0, 53.5, 52.1, 50.0, 41.7, 35.2, 29.2, 21.9, 20.8, 17.6. IR (neat) cm -1 2962, 2923, 2815, 1720, 1609, 1461, 1434, 1415, 1377, 1362, 1333, 1310, 1275, 1203, 1178, 1150, 1106, 1019, 967, 868, 835, 802, 752, 704. HRMS (ESI+): C 17 H 26 NO2[M + H] + : calcd: 276.1958, found: 276.1959.

[0101] Example 12

[0102] Compound III-12

[0103] The preparation method of (methyl 4-((1-isopropyl-2,2-dimethyl-4-phenylazetidin-3-yl)methyl)benzoate) is as follows:

[0104] Same as Example 11, except that R 0 is phenyl. The final product yield is 72%, and the dr value is greater than 20:1.

[0105] Structure characterization data of the product: 1 H NMR(CDCl3,400MHz)δ7.84(d,J=8.0Hz,2H),7.38(d,J=8.0Hz,2H),7.26-7.10(m,4H),3.88(s,3H),3.65(d,J=8.0Hz,1H),2.83-2.73(m,3H),2.25-2.19(m,1H),1.25(s,3H),1.19(s,3H),0.98(d,J=8.0Hz,3H),0.54(d,J=8.0Hz,3H). 13 C NMR(CDCl3,100MHz):δ167.2,145.9,145.6,129.6,128.8,128.0,127.9,127.0,126.8,69.5,61.8,52.8,52.1,50.5,34.4,33.0,23.4,22.2,15.3.IR(neat)cm -1 3060,3027,2964,2869,2817,1720,1609,1574,1492,1452,1434,1415,1380,1361,1328,1275,1199,1179,1152,1106,1020,970,915,862,836,801,763,750,699.HRMS(ESI+):C 23 H 30 NO2[M+H] + :calcd:352.2271,found:352.2272.

[0106] Example 13

[0107] Compound III-13

[0108] (The preparation method of methyl 4-((4-(4-chlorophenyl)-1-isopropyl-2,2-dimethylazetidin-3-yl)methyl)benzoate) is as follows:

[0109] Same as Example 11, except that R 0 is 4-chlorophenyl. The yield of the final product is 70%, and the dr value is greater than 20:1.

[0110] Structure characterization data of the product: 1 H NMR(CDCl3,400MHz)δ7.84(d,J=8.0Hz,2H),7.28(d,J=8.0Hz,2H),7.18-7.11(m,4H),3.88(s,3H),3.62(d,J=8.0Hz,1H),2.82-2.69(m,3H),2.14(q,J=8.0Hz,1H),1.24(s,3H),1.19(s,3H),0.95(d,J=8.0Hz,3H),0.51(d,J=8.0Hz,3H). 13 C NMR(CDCl3,100MHz):δ167.2,145.6,144.2,132.2,129.7,128.8,128.3,128.1,127.9,68.6,61.9,52.9,52.2,50.4,34.4,33.0,23.4,22.2,15.4.IR(neat)cm -1 2964,2870,2841,1720,1609,1488,1464,1434,1380,1363,1326,1311,1276,1196,1180,1152,1106,1058,1015,970,861,832,778,757,733,715,702.HRMS(ESI+):C 23 H 29 NO2Cl[M+H] + :calcd:386.1881,found:386.1886.

[0111] Example 14

[0112] The preparation method of compound III-14 is as follows:

[0113]

[0114] Same as Example 11, except that R 3is cyclohexyl, R 5 and R 6 combine to form a cyclohexyl group. The final product yield is 68%, and the dr value is greater than 20:1.

[0115] Structural characterization data of the product: 1 H NMR(CDCl3,400MHz)δ7.94(d,J=8.0Hz,2H),7.26(d,J=8.0Hz,2H),3.90(s,3H),3.09(dd,J=12.0,8.0Hz,1H),2.98-2.91(m,2H),2.86-2.84(m,1H),2.42-2.37(m,1H),2.29-2.24(m,1H),2.12(d,J=8.0Hz,1H),1.96(d,J=8.0Hz,1H),1.76-1.55(m,8H),1.47-0.97(m,10H). 13 C NMR(CDCl3,100MHz):δ167.3,146.7,129.8,128.9,127.9,67.0,57.8,52.1,51.5,40.1,36.0,33.9,32.6,32.6,30.9,26.2,26.0.24.9,24.8,24.7,23.5.IR(neat)cm -1 2925,2852,2814,1721,1610,1435,1414,1368,1347,1310,1275,1105,1020,968,902,867,835,798,762,734,703.HRMS(ESI+):C 23 H 34 NO2[M+H] + :calcd:356.2584,found:356.2586.

[0116] Example 15: Compound III-15

[0117] (methyl 4-((1-ethyl-2-methyl-1-azaspiro[3.5]nonan-3-yl)methyl)benzoate) is prepared as follows:

[0118]

[0119] Same as Example 11, except that R 0 is methyl, R 3 is ethyl, R 5 and R 6Combine to form cyclohexyl. The final product yield is 67%, and the dr value is greater than 20:1.

[0120] Structural characterization data of the product: 1 H NMR(CDCl3,400MHz)δ7.96(d,J=8.0Hz,2H),7.27(d,J=8.0Hz,2H),3.91(s,3H),3.05(dd,J=12.0,8.0Hz,1H),2.76 - 2.60(m,3H),2.47 - 2.42(m,1H),2.05 - 1.97(m,1H),1.81 - 0.94(m,14H),0.65(d,J=8.0Hz,2H). 13 C NMR(CDCl3,100MHz):δ167.3,148.3,146.1,129.8,129.8,129.0,128.5,128.1,127.9,65.4,62.2,53.7,52.1,51.9,49.0,43.8,43.2,39.1,37.2,34.7,34.1,32.7,26.3,26.0,25.4,25.3,23.9,23.7,22.4,21.2,14.9.IR(neat)cm -1 2927,2852,1717,1609,1435,1415,1375,1277,1178,1108,1049,1019,967,866,763,728.HRMS(ESI+):C 20 H 30 NO2[M + H] + :calcd:316.2271,found:316.2273.

[0121] Example 16: Compound IV - 1

[0122] (methyl 4 - ((1 - isopropyl - 2,2 - dimethyl - 4 - propylazetidin - 3 - yl)methyl)benzoate) is prepared as follows:

[0123] As shown in Reaction Scheme C, under the protection of an inert gas, at room temperature, copper complex [(DPEphos)(bcp)Cu]PF6(0.010 mmol, 5 mol%)(PS4), alkylamine of formula IV - 1(0.4 mmol, 2.0 equiv, where R 5 and R 6The alkyne shown in Formula II (0.2 mmol, 1 equiv, where R 1 is 4-(methoxycarbonyl)phenyl) and the aldehyde shown in Formula V (0.4 mmol, 2.0 equiv, where R 4 is ethyl and R 8 is H) were added to a 3 mL reaction flask, dissolved in anhydrous acetonitrile, the bottle cap was covered, sealed with a sealing film, and then placed under a Blue LED for reaction for 24 h. After the reaction was completed, it was filtered through diatomaceous earth. The filtrate was concentrated and then separated by column chromatography to obtain the final product VI-1 with a yield of 63% and a dr value greater than 20:1.

[0124]

[0125] Structure characterization data of the product: 1 1H NMR (CDCl3, 400 MHz) δ 7.94 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 3.90 (s, 3H), 2.81 - 2.71 (m, 4H), 2.16 (q, J = 8.0 Hz, 1H), 1.25 - 0.82 (m, 19H). 13 13C NMR (CDCl3, 100 MHz): δ 167.2, 146.5, 129.7, 128.8, 127.9, 65.2, 62.2, 52.1, 50.0, 48.8, 40.8, 35.8, 33.0, 23.4, 22.0, 19.0, 16.0, 14.7. IR (neat) cm -1 2957, 2920, 2870, 1720, 1644, 1608, 1574, 1434, 1416, 1377, 1361, 1328, 1275, 1199, 1179, 1150, 1106, 1018, 968, 911, 858, 757, 731, 703, 639. HRMS (ESI+): C 20 H 32 NO2[M + H] + : calcd: 318.2428, found: 318.2428.

[0126] Example 17: Compound IV-2

[0127] (methyl 4-((1-isopropyl-2,2-dimethyl-4-pentylazetidin-3-yl)methyl)benzoate) was prepared as follows:

[0128] Same as Example 16, except that R 4 is butyl. The yield of the final product is 65%, and the dr value is greater than 20:1.

[0129] Structural characterization data of the product: 1 H NMR(CDCl3,400MHz)δ7.94(d,J=8.0Hz,2H),7.27(d,J=8.0Hz,2H),3.90(s,3H),2.88 - 2.61(m,4H),2.16(q,J=8.0Hz,1H),1.24 - 0.81(m,23H). 13 CNMR(CDCl3,100MHz):δ167.2,146.6,129.7,128.8,127.9,65.4,62.0,52.1,49.9,48.9,38.5,35.8,33.0,32.2,25.4,23.4,22.6,22.0,16.0,14.1.IR(neat)cm -1 2956,2928,2857,1721,1609,1435,1415,1377,1361,1309,1275,1179,1150,1107,1019,968,758,728,703.HRMS(ESI+):C 22 H 36 NO2[M + H] + :calcd:346.2741,found:346.2730.

[0130] Example 18: Compound IV - 3

[0131] (methyl 4 - ((4 - cyclohexyl - 1 - isopropyl - 2,2 - dimethylazetidin - 3 - yl)methyl)benzoate) is prepared as follows:

[0132] Same as Example 16, except that in the aldehyde shown in Formula V, R 4 and R 5 are combined into cyclohexane. The yield of the final product is 55%, and the dr value is greater than 20:1.

[0133] Structural characterization data of the product: 11H NMR (CDCl3, 400 MHz) δ 7.94 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 3.90 (s, 3H), 2.87 - 2.68 (m, 4H), 2.29 (q, J = 8.0 Hz, 1H), 2.12 - 2.09 (m, 1H), 1.79 - 1.65 (m, 4H), 1.47 - 1.40 (m, 2H), 1.25 - 0.69 (m, 16H). 13 13C NMR (CDCl3, 100 MHz): δ 167.3, 147.1, 129.7, 128.8, 127.8, 69.6, 61.2, 52.1, 49.7, 42.4, 42.2, 36.5, 33.0, 31.0, 27.9, 27.2, 26.6, 23.9, 22.0, 16.0. IR (neat) cm -1 2921, 2849, 1721, 1609, 1573, 1434, 1414, 1379, 1361, 1308, 1275, 1178, 1152, 1105, 1039, 1019, 970, 909, 889, 873, 852, 838, 802, 754, 733, 703, 607. HRMS (ESI+): C 23 H 36 NO2 [M + H] + : calcd: 358.2714, found: 352.2727.

[0134] Example 19

[0135] The preparation method of compound IV - 4 (methyl 4 - ((1,4 - diisopropyl - 2,2 - dimethylazetidin - 3 - yl)methyl)benzoate) is as follows:

[0136]

[0137] Same as Example 16, except that R 4 and R 5 are methyl groups respectively. The yield of the final product is 53%, and the dr value is greater than 20:1.

[0138] Structure characterization data of the product: 1HNMR(CDCl3, 400 MHz) δ 7.93 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 3.90 (s, 3H), 2.85 - 2.72 (m, 4H), 2.24 (q, J = 8.0 Hz, 1H), 1.77 - 1.73 (m, 2H), 1.26 - 0.67 (m, 18H). 13 C NMR(CDCl3, 100 MHz): δ 167.3, 147.2, 129.7, 128.8, 127.9, 70.0, 61.2, 52.1, 49.5, 41.4, 36.6, 32.9, 31.1, 24.0, 22.0, 19.8, 16.7, 16.1. IR(neat) cm -1 2955, 2869, 2805, 1721, 1609, 1462, 1434, 1414, 1378, 1362, 1315, 1274, 1178, 1150, 1106, 1051, 1018, 969, 855, 837, 799, 776, 755, 725, 702, 613. HRMS(ESI+): C 20 H 32 NO2[M + H] + : calcd: 318.2428, found: 318.2423.

[0139] Example 20: Compound IV - 5

[0140] (methyl 4 - ((4 - isobutyl - 1 - isopropyl - 2,2 - dimethylazetidin - 3 - yl)methyl)benzoate) was prepared as follows:

[0141] Same as Example 16, except that R 4 is isopropyl. The final product yield was 65%, and the dr value was greater than 20:1.

[0142] Structural characterization data of the product: 1 H NMR(CDCl3, 400 MHz) δ 7.94 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 3.90 (s, 3H), 2.88 - 2.61 (m, 4H), 2.18 (q, J = 8.0 Hz, 1H), 1.59 - 0.74 (m, 21H). 13CNMR (CDCl3, 100 MHz): δ 167.1, 146.5, 129.7, 128.7, 127.9, 63.5, 62.1, 52.1, 49.9, 49.6, 48.7, 35.7, 33.2, 25.2, 24.7, 23.5, 22.2, 22.1, 16.0. IR (neat) cm -1 2954, 2928, 2868, 1720, 1609, 1463, 1434, 1415, 1381, 1363, 1310, 1275, 1179, 1149, 1107, 1019, 968, 912, 860, 754, 731, 703. HRMS (ESI+): C 21 H 34 NO2[M + H] + : calcd: 332.2584, found: 332.2582.

[0143] Example 21: Compound IV - 6

[0144] (methyl 4 - ((4 - (4 - chlorobutyl) - 1 - isopropyl - 2,2 - dimethylazetidin - 3 - yl)methyl)benzoate) was prepared as follows:

[0145] Same as Example 16, except that R 4 was 3 - chloropropyl. The final product yield was 65%, and the dr value was greater than 20:1.

[0146] Structural characterization data of the product: 1 H NMR (CDCl3, 400 MHz) δ 7.90 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 3.85 (s, 3H), 3.40 - 3.36 (m, 2H), 2.83 - 2.56 (m, 4H), 2.10 (q, J = 8.0 Hz, 1H), 1.63 - 0.87 (m, 18H). 13 C NMR (CDCl3, 100 MHz): δ 167.1, 146.3, 129.7, 128.7, 127.9, 65.0, 62.0, 52.1, 50.0, 48.6, 44.9, 37.3, 35.6, 32.9, 32.8, 23.4, 22.7, 21.9, 16.0. IR (neat) cm -1 2952,2865,1718,1608,1435,1415,1362,1309,1276,1180,1151,1107,1018,911,730,647. HRMS(ESI+): C 21 H 33 NO2Cl[M + H] + : calcd: 366.2194, found: 366.2195.

[0147] Example 22: Compound IV-7

[0148] (methyl 4-((1-isopropyl-4-(3-methoxy-3-oxopropyl)-2,2-dimethylazetidin-3-yl)methyl)benzoate) was prepared as follows:

[0149] Same as Example 16, except that R 4 is methyl acetate group. The final product yield was 62%, and the dr value was greater than 20:1.

[0150] Structure characterization data of the product: 1 H NMR(400 MHz, CDCl3) δ 7.84(d, J = 8.1 Hz, 2H), 7.16(d, J = 8.0 Hz, 2H), 3.79(s, 3H), 3.62 - 3.52(m, 6H), 2.87 - 2.79(m, 1H), 2.68 - 2.56(m, 3H), 2.22 - 2.20(m, 1H), 2.02 - 1.97(m, 1H), 1.68 - 1.61(m, 1H), 1.02(d, J = 16.2 Hz, 6H), 0.84 - 0.80(m, 6H). 13 C NMR(101 MHz, CDCl3): δ 174.2, 166.8, 146.0, 129.6, 128.6, 127.9, 63.7, 61.8, 51.9, 51.3, 49.4, 47.0, 35.2, 32.6, 31.3, 29.3, 23.3, 21.5, 15.9. IR(neat) cm -1 2953,2872,2845,1719,1608,1435,1363,1276,1175,1106,1018,966,915,857,759,731,706. HRMS(ESI+): C 21 H 32 NO4[M + H] +: calcd: 362.2326, found: 362.22322.

[0151] Example 23: Compound IV-8

[0152] (methyl 4-((1-isopropyl-2,2-dimethyl-4-phenethylazetidin-3-yl)methyl)benzoate) was prepared as follows:

[0153] Same as Example 16, except that R 4 is benzyl. The final product was obtained with a yield of 68% and a dr value greater than 20:1.

[0154] Structural characterization data of the product: 1 H NMR (CDCl3, 400 MHz) δ 7.95 (d, J = 8.0 Hz, 2H), 7.27 - 7.05 (m, 7H), 3.89 (s, 3H), 2.88 - 2.68 (m, 4H), 2.58 - 2.50 (m, 1H), 2.44 - 2.35 (m, 1H), 2.24 (q, J = 8.0 Hz, 1H), 1.84 - 1.80 (m, 2H), 1.14 - 0.92 (m, 12H). 13 C NMR (CDCl3, 100 MHz): δ 167.1, 146.4, 142.5, 129.8, 128.8, 128.3, 128.2, 128.0, 125.6, 64.9, 62.1, 52.0, 49.8, 48.3, 39.1, 35.5, 32.9, 31.6, 23.4, 21.9, 16.0. IR (neat) cm -1 3026, 2952, 2862, 1717, 1606, 1494, 1452, 1435, 1380, 1363, 1277, 1180, 1180, 1153, 1107, 1019, 966, 908, 729, 698. HRMS (ESI+): C 25 H 34 NO2 [M + H] + : calcd: 380.2584, found: 352.2585.

[0155] Example 24

[0156] The preparation method of compound IV-9 (methyl 4-((1-isopropyl-2,2-dimethyl-4-(2-(5-methylfuran-2-yl)ethyl)azetidin-3-yl)methyl)benzoate) is as follows:

[0157]

[0158] Same as Example 16, except that R 4 is The yield of the final product is 70%, and the dr value is greater than 20:1.

[0159] Structure characterization data of the product: 1 H NMR(400MHz,CDCl3)δ7.94(d,J=8.0Hz,2H),7.25(d,J=8.0Hz,2H),5.78(d,J=16.0Hz,2H),3.87(s,3H),2.89-2.71(m,4H),2.56-2.48(m,1H),2.40-2.34(m,1H),2.32-2.15(m,5H),1.85-1.80(m,1H),1.13-0.92(m,12H). 13 C NMR(100MHz,CDCl3):δ166.9,154.1,149.9,146.2,129.6,128.6,127.8,105.7,105.1,64.3,61.9,51.9,49.6,48.0,35.4,35.3,32.8,23.8,23.3,21.7,15.9,13.4.IR(neat)cm -1 2959,2923,2869,1719,1608,1567,1435,1435,1382,1361,1276,1217,1179,1153,1108,1019,963,910,857,777,730,709,646.HRMS(ESI+):C 24 H 34 NO3[M+H] + :calcd:384.2533,found:384.2532.

[0160] Example 25: Compound IV-10

[0161] The preparation method of (methyl 4-((4-(2,6-dimethylhept-5-en-1-yl)-1-isopropyl-2,2-dimethylazetidin-3-yl)methyl)benzoate) is as follows:

[0162] Same as Example 16, except that R 4 is Finally, the product yield is 58%, and the dr value is greater than 20:1.

[0163] Structure characterization data of the product: 1 H NMR(400MHz,CDCl3)δ7.93(d,J=8.0Hz,2H),7.26(d,J=8.0Hz,2H),5.07(t,J=8.0Hz,1H),3.89(s,3H),2.92-2.69(m,4H),2.27-2.19(m,1H),1.97-1.82(m,3H),1.65-1.58(m,6H),1.41-0.82(m,20H). 13 C NMR(101MHz,CDCl3)δ167.2,131.5,129.8,128.7,128.0,125.1,124.8,63.7,62.7,52.1,50.1,49.4,38.7,36.2,35.5,29.7,29.5,25.9,25.6,25.3,21.3,17.8,17.8,16.2.IR(neat)cm -1 2962,2920,2853,1722,1610,1462,1435,1415,1377,1361,1309,1276,1192,1179,1150,1107,1019,969,836,799,754,701.HRMS(ESI+):C 26 H 42 NO2[M+H] + :calcd:400.3210,found:400.3215.

[0164] Example 26: Compound IV-11

[0165] (methyl 4-((1-isopropyl-2-propyl-1-azaspiro[3.5]nonan-3-yl)methyl)benzoate) The preparation method is as follows:

[0166] Same as Example 16, except that R 5 and R 6 combine to form a cyclohexyl group. The final product yield is 65%, and the dr value is greater than 20:1.

[0167] Structural characterization data of the product: 1 HNMR(CDCl3, 400MHz) δ7.94(d, J = 8.0Hz, 2H), 7.27(d, J = 8.0Hz, 2H), 3.90(s, 3H), 3.10(dd, J = 4.0, 4.0Hz, 1H), 2.88 - 2.68(m, 3H), 2.15 - 2.08(m, 1H), 1.77 - 0.82(m, 21H), 0.61(t, J = 8.0Hz, 2H). 13 C NMR(CDCl3, 100MHz): δ167.3, 146.6, 129.7, 129.1, 128.0, 64.8, 63.8, 52.1, 48.4, 48.0, 43.5, 39.5, 37.6, 26.9, 25.9, 24.4, 24.1, 23.6, 21.8, 18.0, 14.7. IR(neat) cm -1 2927, 2853, 2817, 1720, 1608, 1573, 1434, 1414, 1378, 1363, 1308, 1275, 1178, 1143, 1105, 1018, 967, 899, 858, 838, 800, 761, 703, 675. HRMS(ESI+): C 23 H 36 NO2[M + H] + : calcd: 358.2741, found: 358.2738.

[0168] Example 27: Compound IV - 12

[0169]

[0170] Same as Example 16, except that R 1 is 4 - cyanophenyl, and the yield is 61%. The final product yield is 65%, and the dr value is greater than 20:1.

[0171] Structural characterization data of the product: 11H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 2.80 - 2.69 (m, 4H), 2.12 (q, J = 8.0 Hz, 1H), 1.54 - 0.80 (m, 19H). 13 13C NMR (CDCl3, 100 MHz): δ 149.0, 132.3, 129.6, 119.2, 110.0, 65.1, 61.9, 49.9, 48.7, 41.2, 36.0, 33.2, 23.6, 22.0, 18.9, 16.1, 14.7. IR (neat) cm -1 2960, 2870, 2822, 1720, 1606, 1463, 1434, 1414, 1378, 1361, 1329, 1282, 1202, 1149, 1109, 1020, 972, 938, 824, 777, 731, 694. HRMS (ESI+): C 19 H 29 N2[M + H]+: calcd: 285.2325, found: 285.2329.

[0172] : Examples 28 - 39

[0173] Same as Example 1, except that in the alkyne shown in Formula II, R 1 is different, and the product structure is as shown in III - a.

[0174] Table 1: Product structures and their yield data in Examples 28 - 39

[0175]

[0176]

[0177] Product in Example 28: 1 - isopropyl - 2,2,4 - trimethyl - 3 - (4 - (trifluoromethyl)benzyl)azetidine (4c)

[0178] Structure characterization data: 11H NMR (CDCl3, 400 MHz) δ 7.52 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 2.88 - 2.81 (m, 1H), 2.76 - 2.69 (m, 2H), 2.63 (dd, J = 12.0, 8.0 Hz, 1H), 1.95 (q, J = 8.0 Hz, 1H), 1.20 (s, 3H), 1.16 (s, 3H), 0.97 - 0.93 (m, 9H). 13 13C NMR (CDCl3, 100 MHz): δ 144.9, 129.1, 128.4 (q, J = 32.0 Hz), 125.3 (q, J = 3.0 Hz), 124.4 (q, J = 270.0 Hz), 62.5, 61.1, 50.7, 50.1, 34.6, 32.9, 23.8, 23.4, 21.9, 15.8. 19 19F NMR (376 MHz, CDCl3) δ 62.33 (s, 3F). IR (neat) cm -1 2966, 2927, 2872, 2819, 1735, 1464, 1416, 1375, 1304, 1247, 1182, 1146, 1097, 1031, 961, 939, 855, 803, 719. HRMS (ESI+): C 17 H 25 NF3[M + H] + : calcd: 300.1934, found: 300.1933.

[0179] The product in Example 29, 1 - isopropyl - 2,2,4 - trimethylazetidin - 3 - yl)methyl)benzonitrile

[0180]

[0181] Structure characterization data: 1 1H NMR (CDCl3, 400 MHz) δ 7.56 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 2.85 - 2.80 (m, 1H), 2.75 - 2.70 (m, 2H), 2.63 (dd, J = 12.0, 8.0 Hz, 1H), 1.92 (q, J = 8.0 Hz, 1H), 1.19 (s, 3H), 1.15 (s, 3H), 0.95 - 0.92 (m, 9H). 1313C NMR (CDCl3, 100 MHz): δ 146.5, 132.3, 129.6, 119.1, 110.0, 62.6, 61.1, 50.6, 50.1, 35.0, 32.9, 23.8, 23.4, 22.0, 15.9. IR (neat) cm -1 2964, 2924, 2868, 1607, 1504, 1464, 1414, 1381, 1363, 1329, 1260, 1238, 1211, 1191, 1150, 1090, 1019, 858, 800. HRMS (ESI+): C 17 H 25 N2[M + H] + : calcd: 257.2012, found: 257.2010.

[0182] Product in Example 30: 1 - isopropyl - 2,2,4 - trimethylazetidin - 3 - yl)methyl)benzonitrile

[0183]

[0184] Structure characterization data: 1 1H NMR (CDCl3, 400 MHz) δ 7.61 (d, J = 8.0 Hz, 1H), 7.52 - 7.49 (m, 1H), 7.34 - 7.27 (m, 2H), 2.98 - 2.72 (m, 4H), 1.99 (q, J = 8.0 Hz, 1H), 1.25 (s, 3H), 1.22 (s, 3H), 0.96 - 0.89 (m, 9H). 13 13C NMR (CDCl3, 100 MHz): δ 144.7, 133.0, 132.8, 129.8, 126.7, 118.3, 112.6, 62.6, 60.9, 50.5, 50.1, 33.1, 32.7, 23.8, 23.4, 22.0, 16.0. IR (neat) cm -1 2963, 2923, 2867, 2825, 2224, 1599, 1485, 1450, 1381, 1363, 1329, 1303, 1259, 1238, 1209, 1191, 1150, 1076, 1036, 958, 936, 801, 760, 719. HRMS (ESI+): C 17 H 25 N2[M + H] +:calcd:257.2012,found:257.2014.

[0185] Product in Example 31:

[0186] N,N-diethyl-4-((1-isopropyl-2,2,4-trimethylazetidin-3-yl)methyl)benzenesulfonamide

[0187]

[0188] Structure characterization data: 1 H NMR(CDCl3,400MHz)δ7.69(d,J = 8.0Hz,2H),7.28(d,J = 8.0Hz,2H),3.21(q,J = 8.0Hz,4H),2.85 - 2.78(m,1H),2.73 - 2.68(m,2H),2.61(dd,J = 16.0,8.0Hz,1H),1.91(q,J = 8.0Hz,1H),1.17(s,3H),1.14(s,3H),1.07(t,J = 8.0Hz,6H),0.93 - 0.89(m,9H). 13 C NMR(CDCl3,100MHz):δ145.6,138.1,129.4,127.2,62.6,61.0,50.7,50.1,41.9,34.6,32.8,23.7,23.3,21.9,15.9,14.1.IR(neat)cm -1 2965,2871,1598,1493,1465,1408,1382,1353,1332,1270,1238,1120,1153,1090,1016,930,858,784,704.HRMS(ESI+):C 20 H 25 N2O2S[M + H] + :calcd:367.2414,found:367.2418.

[0189] Product in Example 32:

[0190] N,N-diethyl-4-((1-isopropyl-2,2,4-trimethylazetidin-3-yl)methyl)benzamide

[0191]

[0192] Structural characterization data: 1 H NMR(CDCl3, 400 MHz) δ 7.29 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 3.53 (s, 2H), 3.25 (s, 2H), 2.87 - 2.81 (m, 1H), 2.76 - 2.66 (m, 1H), 2.60 (dd, J = 16.0, 8.0 Hz, 1H), 1.96 (q, J = 8.0 Hz, 1H), 1.26 - 1.09 (m, 12H), 0.97 - 0.93 (m, 9H). 13 C NMR(CDCl3, 100 MHz): δ 171.5, 141.9, 134.9, 128.7, 126.6, 62.6, 61.2, 50.7, 50.1, 43.5, 39.4, 34.5, 32.9, 23.8, 23.4, 22.0, 15.9, 14.3, 13.0. IR(neat) cm -1 2966, 2932, 2872, 2825, 1624, 1567, 1511, 1457, 1426, 1380, 1363, 1314, 1286, 1238, 1217, 1189, 1150, 1094, 1020, 921, 875, 855, 832, 804, 757, 728. HRMS(ESI+): C 21 H 35 N2O[M + H] + : calcd: 331.2744, found: 331.2737.

[0193] Product in Example 33: 1 - isopropyl - 3 - (4 - methoxybenzyl) - 2,2,4 - trimethylazetidine

[0194]

[0195] Structural characterization data: 1 H NMR(CDCl3, 400 MHz) δ 7.07 (d, J = 8.0 Hz, 2H), 6.80 (d, J = 8.0 Hz, 2H), 3.77 (s, 3H), 2.84 - 2.77 (m, 1H), 2.75 - 2.68 (m, 1H), 2.60 (dd, J = 16.0, 8.0 Hz, 1H), 2.51 (dd, J = 16.0, 8.0 Hz, 1H), 1.90 (q, J = 8.0 Hz, 1H), 1.19 (s, 3H), 1.15 (s, 3H), 0.97 - 0.92 (m, 9H). 1313C NMR(CDCl3, 100 MHz): δ 157.9, 132.6, 129.7, 113.8, 62.5, 61.3, 55.3, 51.0, 50.1, 33.7, 32.9, 23.8, 23.4, 22.0, 15.8. IR(neat) cm -1 2962, 2927, 2868, 2833, 1611, 1583, 1510, 1462, 1380, 1362, 1327, 1298, 1244, 1216, 1177, 1150, 1108, 1076, 1037, 958, 937, 823, 802, 747, 716. HRMS(ESI+): C 17 H 28 NO[M + H] + : calcd: 262.2165, found: 262.2167.

[0196] Product in Example 34: 3-(4-(tert-butyl)benzyl)-1-isopropyl-2,2,4-trimethylazetidine

[0197]

[0198] Structure characterization data: 1 1H NMR(CDCl3, 400 MHz) δ 7.27(d, J = 8.0 Hz, 2H), 7.09(d, J = 8.0 Hz, 2H), 2.85 - 2.78(m, 1H), 2.75 - 2.69(m, 1H), 2.63(dd, J = 12.0, 8.0 Hz, 1H), 2.53(dd, J = 12.0, 8.0 Hz, 1H), 1.95(q, J = 8.0 Hz, 1H), 1.29(s, 9H), 1.21(s, 3H), 1.16(s, 3H), 0.98 - 0.92(m, 9H). 13 13C NMR(CDCl3, 100 MHz): δ 148.7, 137.4, 128.4, 125.2, 62.5, 61.3, 50.7, 50.1, 34.4, 34.0, 32.9, 31.5, 23.8, 23.4, 22.0, 15.8. IR(neat) cm -1 2962,2868,2813,1514,1462,1412,1380,1363,1328,1268,1237,1214,1150,1108,1089,1075,1019,959,933,873,841,823,803,718. HRMS(ESI+): C 20 H 34 N[M+H] + : calcd: 288.2686, found: 288.2694

[0199] Product in Example 35: 1-isopropyl-2,2,4-trimethyl-3-(4-methylbenzyl)azetidine

[0200]

[0201] Structure characterization data: 1 H NMR(CDCl3, 400 MHz) δ 7.08 - 7.06(m, 4H), 2.83 - 2.78(m, 1H), 2.75 - 2.69(m, 1H), 2.62(dd, J = 16.0, 8.0 Hz, 1H), 2.53(dd, J = 16.0, 8.0 Hz, 1H), 2.30(s, 3H), 1.93(q, J = 8.0 Hz, 1H), 1.19(s, 3H), 1.15(s, 3H), 0.98 - 0.92(m, 9H). 13 C NMR(CDCl3, 100 MHz): δ 137.4, 135.3, 129.1, 128.7, 62.5, 61.3, 50.9, 50.1, 34.2, 32.9, 23.8, 23.4, 22.0, 21.2, 15.8. IR(neat) cm -1 2963,2922,2867,2814,1514,1451,1380,1362,1328,1298,1268,1237,1212,1190,1150,1107,1076,1021,959,932,909,873,848,805,791,734,715. HRMS(ESI+): C 17 H 28 N[M+H] + : calcd: 246.2216, found: 246.2218.

[0202] Product in Example 36: 3-(4-bromobenzyl)-1-isopropyl-2,2,4-trimethylazetidine

[0203]

[0204] Structure characterization data: 1 H NMR(CDCl3,400MHz)δ7.38(d,J=8.0Hz,2H),7.05(d,J=8.0Hz,2H),2.85-2.78(m,1H),2.75-2.69(m,1H),2.61(dd,J=12.0,8.0Hz,1H),2.53(dd,J=16.0,8.0Hz,1H),1.91(q,J=8.0Hz,1H),1.19(s,3H),1.15(s,3H),0.98-0.92(m,9H). 13 CNMR(CDCl3,100MHz):δ139.6,131.5,130.6,119.7,62.5,61.2,50.8,50.1,34.1,32.9,23.8,23.4,22.0,15.9.IR(neat)cm -1 2962,2922,2854,2822,1487,1452,1403,1380,1362,1327,1298,1267,1236,1212,1191,1150,1102,1072,1010,959,932,873,849,795,749,718.HRMS(ESI+):C 16 H 25 NBr[M+H] + :calcd:310.1165,found:310.1165.

[0205] Product in Example 37: 3-(3-chlorobenzyl)-1-isopropyl-2,2,4-trimethylazetidine

[0206]

[0207] Structure characterization data: 11H NMR (CDCl3, 400 MHz) δ 7.20 - 7.14 (m, 3H), 7.06 - 7.04 (m, 1H), 2.85 - 2.79 (m, 1H), 2.75 - 2.69 (m, 1H), 2.63 (dd, J = 12.0, 8.0 Hz, 1H), 2.54 (dd, J = 12.0, 8.0 Hz, 1H), 1.91 (q, J = 8.0 Hz, 1H), 1.20 (s, 3H), 1.15 (s, 3H), 0.98 - 0.92 (m, 9H). 13 13C NMR (CDCl3, 100 MHz): δ 142.7, 134.1, 129.6, 128.9, 126.9, 126.1, 62.4, 61.1, 50.6, 50.1, 34.4, 32.9, 23.8, 23.4, 21.9, 15.8. IR (neat) cm -1 2964, 2921, 2868, 2814, 1597, 1573, 1474, 1450, 1429, 1380, 1362, 1327, 1302, 1267, 1237, 1207, 1190, 1150, 1077, 1000, 958, 937, 911, 881, 865, 775, 750, 719. HRMS (ESI+): C 16 H 25 NCl [M + H] + : calcd: 266.1670, found: 266.1665.

[0208] Product in Example 38: 3-(2-fluorobenzyl)-1-isopropyl-2,2,4-trimethylazetidine

[0209]

[0210] Structure characterization data: 1 1H NMR (CDCl3, 400 MHz) δ 7.17 - 7.10 (m, 2H), 7.03 - 6.94 (m, 2H), 2.87 - 2.81 (m, 1H), 2.74 - 2.64 (m, 2H), 2.58 (dd, J = 12.0, 8.0 Hz, 1H), 1.93 (q, J = 8.0 Hz, 1H), 1.20 (s, 3H), 1.16 (s, 3H), 0.94 - 0.90 (m, 9H). 1313C NMR(CDCl3, 100 MHz): δ 161.1 (d, J = 243.0 Hz), 130.9 (d, J = 6.0 Hz), 127.6 (d, J = 8.0 Hz), 127.4, 123.9 (d, J = 3.0 Hz), 115.3 (d, J = 23.0 Hz), 62.4, 61.2, 50.1, 49.7, 32.7, 27.4 (d, J = 1.0 Hz), 23.7, 23.3, 21.9, 15.7. 19 19F NMR(376 MHz, CDCl3) δ -118.47 (s, 1F). IR(neat) cm -1 2964, 2922, 2867, 2816, 1584, 1492, 1453, 1363, 1328, 1268, 1229, 1191, 1150, 1101, 1031, 937, 844, 752, 717. HRMS(ESI+): C 16 H 25 NF[M + H] + : calcd: 250.1965, found: 250.1968.

[0211] Product in Example 39: 3-(4-fluorobenzyl)-1-isopropyl-2,2,4-trimethylazetidine

[0212]

[0213] Structure characterization data: 1 1H NMR(CDCl3, 400 MHz) δ 7.12 - 7.08 (m, 2H), 6.94 - 6.90 (m, 2H), 2.82 - 2.76 (m, 1H), 2.74 - 2.67 (m, 1H), 2.61 (dd, J = 16.0, 8.0 Hz, 1H), 2.52 (dd, J = 16.0, 8.0 Hz, 1H), 1.88 (q, J = 8.0 Hz, 1H), 1.17 (s, 3H), 1.13 (s, 3H), 0.94 - 0.90 (m, 9H). 13 13C NMR(CDCl3, 100 MHz): δ 160.2 (d, J = 242.0 Hz), 135.0 (d, J = 3.0 Hz), 128.9 (d, J = 8.0 Hz), 114.0 (d, J = 21.0 Hz), 61.3, 60.0, 49.8, 48.9, 32.6, 31.7, 22.6, 22.2, 20.8, 14.7. 19F NMR(376MHz,CDCl3)δ-117.70(s,1F).IR(neat)cm -1 2964,2923,2868,2815,1602,1509,1451,1381,1363,1328,1295,1258,1218,1154,1095,1014,959,927,872,801,760,716.HRMS(ESI+):C 16 H 25 NF[M+H] + :calcd:250.1965,found:250.1969.

[0214] Comparative Example 1

[0215] The preparation method is the same as in Example 1, except that the structure of the alkylamine used is In the end, no azetidine compounds with four-membered ring structures were obtained, only aromatic alkynes and chain alkylamines were obtained.

[0216] Based on the method of the present invention, under blue light irradiation, a copper (I) complex photosensitizer is used as a catalyst to catalyze a free radical reaction between an organic amine and an alkyne to generate an azetidine compound with a four-membered ring structure with high yield and diastereoselectivity. Taking the free radical tandem reaction of a tertiary amine (having at least one α-tertiary carbon) and a variety of alkynes catalyzed by a Cu photosensitizer as an example, a mechanism diagram is drawn, as shown in FIG. Figure 1 As shown, the copper (I) complex photosensitizer reaches an excited state under light conditions, and the excited state photosensitizer oxidizes the alkylamine to generate an alkylamine free radical A (i.e., C (sp 3 )-H activation) and a copper(0) complex (Cu(0)) that obtains an electron, the alkylamine radical A is dehydrogenated to generate an α-amino radical B, the amino radical B is added to an alkyne to generate an olefinic radical intermediate C, and the intermediate C is converted into a tertiary radical intermediate D (i.e., C(sp 3 )-H activation), D then undergoes 4-exo-trig cyclization to generate intermediate E, the excited copper (0) complex reduces intermediate E to obtain the final product 4a, and the copper (I) complex photosensitizer is regenerated to complete the entire catalytic cycle. This method is a dual C (sp 3 A new example was added for the activation of )-H.

[0217] Although the embodiments of the present invention have been described in detail above, those skilled in the art will appreciate that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the claims and their equivalents.

Claims

1. A method for preparing an azetidine compound, characterized in that, Under blue light irradiation, using a copper(I) complex photosensitizer as a photocatalyst, an organic amine and an alkyne are catalyzed to react to form an azetidine compound with a four-membered ring structure. The organic amine is selected from one of secondary amines or tertiary amines, and the copper(I) complex photosensitizer is selected from one of the following structures: The organic amine is a tertiary amine represented by Formula I, and the structure of the azetidine compound is as shown in Formula III. The preparation method of the azetidine compound shown in Formula III includes the following steps: Using the copper(I) complex photosensitizer as a photocatalyst, under blue light irradiation and under the protection of an inert gas, reacting the tertiary amine shown in Formula I and the alkyne shown in Formula II in a first organic solvent to form an azetidine compound with a four-membered ring structure shown in Formula III. The first organic solvent is selected from one of acetonitrile, DMF, THF, 1,4-dioxane or a mixture of any proportion of several of them. Or, The organic amine is a secondary amine represented by Formula IV, and the structure of the azetidine compound is as shown in Formula IV. The preparation of the azetidine compound shown in Formula IV includes the following steps: Using the copper(I) complex photosensitizer as a photocatalyst, under blue light irradiation and under the protection of an inert gas, reacting the secondary amine shown in Formula IV, the terminal alkyne shown in Formula VII and the aldehyde shown in Formula V in a second organic solvent to form an azetidine compound with a four-membered ring structure shown in Formula VI. The second organic solvent is selected from one of acetonitrile, DMF, THF, 1,4-dioxane or a mixture of any proportion of several of them. Among them, R 0 is selected from one of H, methyl, phenyl or chlorophenyl; R 1 is selected from one of substituted or unsubstituted phenyl, substituted or unsubstituted 2-pyridyl, substituted or unsubstituted trimethylsilyl, substituted or unsubstituted formate group, and the substituent is selected from one of trifluoromethyl, nitrile group, sulfonamide group, amide group, alkoxy group, alkyl group or halogen; R 2 is selected from H or methyl; R 3 is selected from one of methyl, ethyl, isopropyl, cyclohexyl; R 8 is H, R 4 is selected from one of methyl, ethyl, propyl, isopropyl or substituted methyl, and when the R 4 is substituted methyl, the substituent is selected from one of phenyl or 2-furyl; R 5 and R 6 are respectively methyl, or combined into cyclohexane; R 7 is isopropyl.

2. The method for preparing an azetidine compound according to claim 1, characterized in that, The molar ratio of the tertiary amine shown in Formula I, the alkyne shown in Formula II and the copper(I) complex photosensitizer is (1-3):1:(2%-8%).

3. The method for preparing an azetidine compound according to claim 1, wherein The molar ratio of the secondary amine shown in Formula IV, the terminal alkyne shown in Formula VII, the aldehyde shown in Formula V and the copper(I) complex photosensitizer is (1-3):1:(1-3):(2%-8%).

4. The preparation method of the azetidine compound according to claim 1, characterized in that, After reacting the tertiary amine shown in Formula I and the alkyne shown in Formula II in the first organic solvent for 6-24 h, filter, and concentrate and subject the filtrate to column chromatography to obtain the azetidine compound with a four-membered ring structure shown in Formula III.

5. The preparation method of the azetidine compound according to claim 4, characterized in that, In the preparation of the azetidine compound with a four-membered ring structure shown in Formula III, the eluent used in column chromatography is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate in the mixed solution is (1:1)-(10:1).

6. The method for preparing an azetidine compound according to claim 1, characterized in that, After reacting the secondary amine shown in Formula IV, the terminal alkyne shown in Formula VII and the aldehyde shown in Formula V in the second organic solvent for 6-24 h, filter, and concentrate and subject the filtrate to column chromatography to obtain the azetidine compound with a four-membered ring structure shown in Formula VI.

Images