CN112552285A - Synthesis method of 4- (2,2, 2-trichloroethyl) -beta-lactam derivative - Google Patents

Synthesis method of 4- (2,2, 2-trichloroethyl) -beta-lactam derivative Download PDF

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CN112552285A
CN112552285A CN202110090246.2A CN202110090246A CN112552285A CN 112552285 A CN112552285 A CN 112552285A CN 202110090246 A CN202110090246 A CN 202110090246A CN 112552285 A CN112552285 A CN 112552285A
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曾润生
甘紫旭
赵应声
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Suzhou University
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Abstract

The invention relates to a preparation method of a 4- (2,2, 2-trichloroethyl) -beta-lactam derivative, which comprises the steps of reacting a substituted N-quinoline-3-butenamide derivative in chloroform at 100-120 ℃ under the action of an oxidant and a copper salt catalyst, and obtaining the 4- (2,2, 2-trichloroethyl) -beta-lactam derivative after the reaction is completed. The method can obtain various 4- (2,2, 2-trichloroethyl) -beta-lactam derivatives in high yield. The method has mild reaction conditions, simple reaction operation and post-treatment process, and is suitable for large-scale production.

Description

Synthesis method of 4- (2,2, 2-trichloroethyl) -beta-lactam derivative
Technical Field
The invention relates to the technical field of preparation of organic compounds, in particular to a synthesis method of a 4- (2,2, 2-trichloroethyl) -beta-lactam derivative.
Background
Beta-lactams are an important component of the N-heterocycle and are the core backbone of many natural products and drug molecules, especially specific drugs for some antibiotics. Therefore, the synthesis of the beta-lactam derivative has important value.
To date, the synthesis of β -lactam derivatives has been mainly as follows:
the synthesis of beta-lactam derivatives is described inJ. Am. Chem. Soc， 1982, 1043233 the method is described by oxidation of the ring.J. Org. Chem. 1995, 601276 discloses a method of preparing beta-lactam derivatives by ring closure reaction by reduction.
A method for synthesizing beta-lactam by utilizing C-H bond activation and metal catalysis respectively inAngewandte Chemie，2013, 52, 13588、Angewandte Chemie 2014, 533496 andChem. Eur. J, 2014, 209530.
In 2019, the group of the inventor isChem. Common.2019,55, 10523 reported a free radical-promoted addition cyclization reaction that synthesized beta-lactams. This reaction has certain technical advantages, however, it is limited to benzyl radical promoted reactions, and it is not suitable for the synthesis of 4- (2,2, 2-trichloroethyl) - β -lactam derivatives.
In summary, the existing method for synthesizing 4- (2,2, 2-trichloroethyl) -beta-lactam derivatives generally uses very expensive raw materials, and has harsh reaction conditions and is not environment-friendly.
Disclosure of Invention
In order to overcome the defects of low yield, use of expensive raw materials, harsh reaction conditions and environmental friendliness of the 4- (2,2, 2-trichloroethyl) -beta-lactam derivative prepared by the prior art, the invention aims to provide the preparation method of the 4- (2,2, 2-trichloroethyl) -beta-lactam derivative, which has the advantages of easily available raw materials, high yield, mild reaction conditions, good universality and environmental protection.
The inventors of the present invention have found through intensive studies that 4- (2,2, 2-trichloroethyl) - β -lactam derivatives can be efficiently synthesized by initiating the trichloromethyl radical ring formation reaction, and 4- (2,2, 2-trichloroethyl) - β -lactam derivatives can be obtained in high yield by reacting substituted N-quinoline-3-butenamide derivatives with chloroform at 100 ℃ and 120 ℃ under the catalysis of copper salt and the oxidation of an oxidizing agent.
Specifically, the technical scheme of the invention is as follows:
a method for preparing a 4- (2,2, 2-trichloroethyl) -beta-lactam derivative, comprising the following steps: reacting the substituted N-quinoline-3-butenamide derivative shown in the formula (1) in chloroform at 100-120 ℃ under the action of an oxidant and a copper salt catalyst, and obtaining a 4- (2,2, 2-trichloroethyl) -beta-lactam derivative shown in the formula (2) after the reaction is completed;
Figure DEST_PATH_IMAGE001
；
wherein R is1Hydrogen, C1-C6 alkyl, phenyl or substituted phenyl;
R2and R3Independently selected from hydrogen, C1-C6 alkyl, phenyl, substituted phenyl or C1-C6 unsaturated alkyl;
and the substituent on the substituted phenyl is one or more of C1-C6 alkyl, halogen and an ester group.
In the invention, trichloromethane is used as a solvent required by the reaction and also used as a reactant.
The reaction route of the method is as follows:
Figure DEST_PATH_IMAGE002
。
the method belongs to a double-bond free radical addition cyclization reaction promoted by trichloromethyl free radical, has mild conditions and meets the requirement of green chemistry.
Further, the C1-C6 alkyl comprises one of substituted or unsubstituted straight-chain alkyl, substituted or unsubstituted branched-chain alkyl and substituted or unsubstituted cycloalkyl; wherein the substituents on the substituted linear alkyl, the substituted branched alkyl and the substituted cyclic alkyl are respectively and independently selected from alkyl and halogen.
Further, R1Is hydrogen, R3Is hydrogen or methyl, R2The alkyl group is hydrogen, unsubstituted C1-C6 linear alkyl, ester group substituted C1-C6 alkyl, allyl, benzyl, phenethyl, cyclopropylmethyl, cyclobutylmethyl, halopropyl, p-tolylethyl or halophenethyl.
Further, R2Is hydrogen, R3Is hydrogen, R1Is C1-C6 alkyl or benzyl.
Further, the oxidizing agent is di-tert-butyl peroxide (DTBP).
Further, the cupric salt catalyst is cuprous bromide (CuBr), cupric acetate (Cu (OAc)2) Cuprous chloride, copper tetraethyl-hexafluorophosphate (Cu (CH)3CN)4PF6) Copper triflate and copper bromide (CuBr)2) One or more of them. Preference is given toThe copper salt catalyst is tetraethyl nitrile copper hexafluorophosphate.
Further, the mol ratio of the substituted N-quinoline-3-butenamide derivative to the chloroform to the oxidant to the copper salt catalyst is 1: 8-12: 3-8: 0.05 to 0.2.
Preferably, the molar ratio of the substituted N-quinoline-3-butenamide derivative, the trichloromethane, the oxidizing agent and the copper salt catalyst is 1:10:6: 0.1.
Preferably, the reaction temperature is 110 ℃.
By the scheme, the invention at least has the following advantages:
1. the invention provides a brand new system, and realizes the synthesis of the 4- (2,2, 2-trichloroethyl) -beta-lactam derivative by utilizing the free radical reaction.
2. The invention uses the substituted N-quinoline-3-butene amide derivative as the starting material, and the raw materials are easy to obtain and have a plurality of varieties; the products obtained by the method of the invention are of various types, and can be directly used and can also be used for other further reactions.
3. The invention has novel reaction, simple reaction operation and post-treatment process and high yield, and is suitable for large-scale production.
The foregoing is a summary of the present invention, and in order to provide a clear understanding of the technical means of the present invention and to be implemented in accordance with the present specification, the following is a preferred embodiment of the present invention and is described in detail below.
Detailed Description
The following examples are given to further illustrate the embodiments of the present invention. The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
The first embodiment is as follows: synthesis of 4- (2,2, 2-trichloroethyl) -1- (8-quinolyl) -beta-lactam
Figure DEST_PATH_IMAGE003
(1) Weighing N- (8-quinolyl) -3-butenamide 1a (0.042 g, 0.2 mmol), Cu (CH)3CN)4PF6(0.008g, 0.02 mmol) was dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 110 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain compound 2 a. The isolated yield was 92%.
(2) Weighing N- (8-quinolyl) -3-butenamide 1a (0.042 g, 0.2 mmol), Cu (CH)3CN)4PF6(0.008g, 0.02 mmol) was dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 100 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain compound 2 a. The isolated yield was 83%.
(3) Weighing N- (8-quinolyl) -3-butenamide 1a (0.042 g, 0.2 mmol), Cu (CH)3CN)4PF6(0.008g, 0.02 mmol) was dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 120 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain compound 2 a. The isolated yield was 41%.
(4) Weighing N- (8-quinolyl) -3-butenamide 1a (0.042 g, 0.2 mmol) and CuBr2(0.005g, 0.02 mmol) was dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 110 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain compound 2 a. The isolated yield was 62%.
(5) N- (8-quinolyl) -3-butenamide 1a (0.042 g, 0.2 mmol), Cu (OAc) were weighed2(0.004g, 0.02 mmol) was dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 110 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain compound 2 a. The isolated yield was 45%.
(6) N- (8-quinolyl) -3-butenamide 1a (0.042 g, 0.2 mmol) and CuBr (0.003g, 0.02 mmol) were dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 110 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain compound 2 a. The isolated yield was 50%.
2a:1H NMR (400 MHz, CDCl3) δ8.84 (dd, J = 4.1, 1.8 Hz, 1H), 8.33 (dd, J = 7.5, 1.4 Hz, 1H), 8.15 (dd, J = 8.4, 1.7 Hz, 1H), 7.60 (dd, J = 8.2, 1.3 Hz, 1H), 7.55 – 7.50 (m, 1H), 7.42 (dd, J = 8.3, 4.1 Hz, 1H), 5.70 – 5.62 (m, 1H), 3.66 (dd, J = 14.3, 1.6 Hz, 1H), 3.57 (dd, J = 15.6, 5.2 Hz, 1H), 3.29 (dd, J = 15.6, 2.6 Hz, 1H), 2.91 (dd, J = 14.3, 10.2 Hz, 1H).; 13C NMR (101 MHz, CDCl3) δ165.82, 149.13, 140.06, 136.13, 132.86, 128.97, 126.82, 124.12, 121.58, 121.17, 96.68, 57.07, 54.23, 45.56; HRMS(ESI-TOF) Calcd for C14H12Cl3N2O [M+H]+:329.0015，found: 329.0013.
Example two: synthesis of 3-methyl-4- (2,2, 2-trichloroethyl) -1- (8-quinolyl) -beta-lactam
Figure DEST_PATH_IMAGE004
N- (8-quinolyl) -2-methyl-3-butenamide 1b (0.045 g, 0.2 mmol), Cu (CH) were weighed3CN)4PF6(0.008g, 0.02 mmol) was dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 110 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain compound 2 b. The isolated yield was 59%.
2b: 1H NMR (400 MHz, CDCl3) δ 8.83 (dd, J = 4.1, 1.8 Hz, 1H), 8.33 (dd, J = 7.5, 1.4 Hz, 1H), 7.59 (dd, J = 8.2, 1.4 Hz, 1H), 7.55 – 7.50 (m, 1H), 7.42 (dd, J = 8.4, 4.1 Hz, 1H), 5.28 (dt, J = 10.2, 2.0 Hz, 1H), 3.64 (dd, J = 14.3, 1.8 Hz, 1H), 3.47 – 3.40 (m, 1H), 2.93 (dd, J = 14.3, 10.2 Hz, 1H), 1.57 (d, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ169.54, 149.11, 140.12, 136.12, 132.77, 129.00, 126.82, 124.03, 121.54, 121.43, 96.62, 62.25, 56.97, 53.02, 13.40；HRMS Calcd for C15H14Cl3N2O [M+H] +: 343.0172, Found: 343.0169.
Example three: synthesis of 3-ethyl-4- (2,2, 2-trichloroethyl) -1- (8-quinolyl) -beta-lactam
Figure DEST_PATH_IMAGE005
N- (8-quinolyl) -2-ethyl-3-butenamide 1c (0.048 g, 0.2 mmol), Cu (CH) were weighed3CN)4PF6(0.008g, 0.02 mmol) was dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 110 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain compound 2 c. The isolated yield was 61%.
2c: 1H NMR (400 MHz, CDCl3) δ8.84 (dd, J = 4.1, 1.8 Hz, 1H), 8.35 (dd, J = 7.5, 1.4 Hz, 1H), 8.14 (dd, J = 8.3, 1.7 Hz, 1H), 7.59 (dd, J = 8.2, 1.3 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 7.42 (dd, J = 8.3, 4.1 Hz, 1H), 5.39 (dt, J = 10.1, 2.0 Hz, 1H), 3.63 (dd, J = 14.3, 1.9 Hz, 1H), 3.46 – 3.41 (m, 1H), 2.94 (dd, J = 14.3, 10.1 Hz, 1H), 2.09 – 1.97 (m, 2H), 1.19 (t, J = 7.5 Hz, 3H)；13C NMR (101 MHz, CDCl3) δ169.09, 149.12, 140.16, 136.09, 132.76, 128.99, 126.82, 123.98, 121.52, 121.35, 96.67, 59.65, 59.01, 56.97, 21.89, 11.22; HRMS Calcd for C16H16Cl3N2O [M+H] +: 357.0328, Found: 357.0321.
Example four: synthesis of 3-isopropyl-4- (2,2, 2-trichloroethyl) -1- (8-quinolyl) -beta-lactam
Figure DEST_PATH_IMAGE006
Weighing N- (8-quinolyl) -2-isopropyl-3-butenamide 1d (0.051 g, 0.2 mmol), Cu (CH)3CN)4PF6(0.008g, 0.02 mmol) was dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 110 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain compound 2 d. The isolated yield was 50%.
2d:1H NMR (400 MHz, CDCl3) δ8.84 (dd, J = 4.1, 1.6 Hz, 1H), 8.36 (dd, J = 7.5, 1.2 Hz, 1H), 8.12 (d, J = 8.2 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.40 (dd, J = 8.3, 4.1 Hz, 1H), 5.45 (dt, J = 9.8, 2.0 Hz, 1H), 3.59 (dd, J = 14.4, 2.1 Hz, 1H), 3.38 (dd, J = 5.6, 2.0 Hz, 1H), 2.93 (dd, J = 14.4, 9.9 Hz, 1H), 2.35 – 2.26 (m, 1H), 1.21 (dd, J = 9.6, 6.9 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 168.40, 149.14, 140.24, 136.06, 132.65, 128.96, 126.80, 123.99, 121.50, 121.37, 96.63, 63.75, 58.41, 57.03, 28.22, 21.52, 18.91; HRMS Calcd for C17H18Cl3N2O [M+H] +: 371.0485,Found: 371.0491.
Example five: synthesis of 3-allyl-4- (2,2, 2-trichloroethyl) -1- (8-quinolyl) -beta-lactam
Figure DEST_PATH_IMAGE007
Weighing N- (8-quinolyl) -2-allyl-3-butylEnamide 1e (0.050 g, 0.2 mmol), Cu (CH)3CN)4PF6(0.008g, 0.02 mmol) was dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 110 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain compound 2 e. The isolated yield was 47%.
2e:1H NMR (400 MHz, CDCl3) δ8.84 (dd, J = 4.1, 1.8 Hz, 1H), 8.34 (dd, J = 7.5, 1.4 Hz, 1H), 8.14 (dd, J = 8.4, 1.8 Hz, 1H), 7.60 (dd, J = 8.2, 1.4 Hz, 1H), 7.55 – 7.50 (m, 1H), 7.42 (dd, J = 8.4, 4.1 Hz, 1H), 6.04 – 5.97 (m, 1H), 5.42 (dt, J = 10.1, 2.1 Hz, 1H), 5.28 – 5.23 (m, 1H), 5.16 – 5.12 (m, 1H), 3.65 (dd, J = 14.3, 1.9 Hz, 1H), 3.56 – 3.51 (m, 1H), 2.95 (dd, J = 14.3, 10.1 Hz, 1H), 2.79 – 2.67 (m, 2H). 13C NMR (101 MHz, CDCl3) δ168.28, 149.15, 140.11, 136.08, 133.89, 132.70, 128.98, 126.81, 124.05, 121.53, 121.35, 118.12, 96.59, 59.24, 57.23, 56.84, 32.68 (s), 120.83 (s), 55.58 (s), 42.68 (s), 33.30 (s), 28.99 (s); HRMS Calcd for C17H15Cl3N2ONa [M+H]+: 391.0148, Found: 391.0148.
Example six: synthesis of 3-benzyl-4- (2,2, 2-trichloroethyl) -1- (8-quinolyl) -beta-lactam
Figure DEST_PATH_IMAGE008
N- (8-quinolyl) -2-benzyl-3-butenamide 1f (0.061 g, 0.2 mmol), Cu (CH) were weighed out3CN)4PF6(0.008g, 0.02 mmol) was dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 110 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain compound 2 f. The isolated yield was 70%.
2f:1H NMR (400 MHz, CDCl3) δ8.79 (dd, J = 4.1, 1.8 Hz, 1H), 8.27 (dd, J = 7.5, 1.3 Hz, 1H), 8.14 – 8.09 (m, 1H), 7.58 (dd, J = 8.2, 1.3 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.42 – 7.35 (m, 3H), 7.32 – 7.25 (m, 2H), 7.22 – 7.17 (m, 1H), 5.40 (dt, J = 10.0, 2.0 Hz, 1H), 3.74 – 3.67 (m, 1H), 3.60 (dd, J = 14.4, 1.9 Hz, 1H), 3.37 – 3.24 (m, 2H), 2.95 (dd, J = 14.4, 10.1 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ168.30, 149.11, 140.19, 137.93, 136.03, 132.59, 129.51, 128.94, 128.51, 126.76, 126.64, 124.19, 121.52, 121.49, 96.51, 59.44, 58.91, 56.85, 34.73; HRMS Calcd for C21H18Cl3N2O [M+H]+: 419.0485, Found: 419.0485.
Example seven: synthesis of 3-phenethyl-4- (2,2, 2-trichloroethyl) -1- (8-quinolyl) -beta-lactam
Figure DEST_PATH_IMAGE009
1g (0.063 g, 0.2 mmol) of N- (8-quinolyl) -2-phenethyl-3-butenamide and Cu (CH) were weighed3CN)4PF6(0.008g, 0.02 mmol) was dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 110 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain 2g of the compound. The isolated yield was 61%.
2g:1H NMR (400 MHz, CDCl3) δ8.82 (dd, J = 4.1, 1.8 Hz, 1H), 8.35 (dd, J = 7.5, 1.4 Hz, 1H), 8.14 (dd, J = 8.4, 1.7 Hz, 1H), 7.60 (dd, J = 8.2, 1.4 Hz, 1H), 7.56 – 7.50 (m, 1H), 7.41 (dd, J = 8.3, 4.1 Hz, 1H), 7.28 – 7.24 (m, 4H), 7.22 – 7.15 (m, 1H), 5.39 (dt, J = 10.1, 2.0 Hz, 1H), 3.61 (dd, J = 14.3, 1.9 Hz, 1H), 3.50 – 3.42 (m, 1H), 3.11 – 3.01 (m, 1H), 2.94 – 2.84 (m, 2H), 2.38 – 2.26 (m, 2H). 13C NMR (101 MHz, CDCl3) δ168.88, 149.14, 141.38, 140.16, 136.12, 132.72, 129.00, 128.56, 128.42, 126.83, 126.03, 124.08, 121.56, 121.37, 96.59, 60.20, 57.01, 56.90, 32.98, 30.74; HRMS Calcd for C22H20Cl3N2O[M+H]+: 433.0641, Found: 433.0646.
Example eight: synthesis of 3-methylcyclopropane-4- (2,2, 2-trichloroethyl) -1- (8-quinolyl) -beta-lactam
Figure DEST_PATH_IMAGE010
N- (8-quinolyl) -2-methylcyclopropane-3-butenamide was weighed for 1h (0.063 g, 0.2 mmol), and Cu (CH)3CN)4PF6(0.008g, 0.02 mmol) was dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 110 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction is finished, the crude product is purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain a compound for 2 h. The isolated yield was 50%.
2h:1H NMR (400 MHz, CDCl3) δ 8.84 (dd, J = 4.1, 1.8 Hz, 1H), 8.36 (dd, J = 7.5, 1.4 Hz, 1H), 8.14 (dd, J = 8.4, 1.7 Hz, 1H), 7.59 (dd, J = 8.2, 1.4 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.42 (dd, J = 8.3, 4.1 Hz, 1H), 5.54 (dt, J = 10.1, 2.0 Hz, 1H), 3.64 (dd, J = 14.3, 1.9 Hz, 1H), 3.58 – 3.52 (m, 1H), 2.94 (dd, J = 14.3, 10.1 Hz, 1H), 1.95 – 1.83 (m, 2H), 1.08 – 0.98 (m, 1H), 0.57 – 0.47 (m, 2H), 0.23 – 0.12 (m, 2H).13C NMR (101 MHz, CDCl3) δ169.14, 149.11, 140.17, 136.08, 132.80, 128.99, 126.83, 123.98, 121.52, 121.34, 96.72, 59.62, 58.08, 57.04, 33.62, 8.42, 5.25, 4.65; HRMS Calcd for C18H18Cl3N2O [M+H+]: 383.0485, Found: 383.0481.
Example nine: synthesis of 3-methylcyclobutane-4- (2,2, 2-trichloroethyl) -1- (8-quinolyl) -beta-lactam
Figure DEST_PATH_IMAGE011
Weighing N- (8-quinolyl) -2-methylcyclobutane-3-butenamide 1i (0.056 g, 0.2 mmol), Cu (CH)3CN)4PF6(0.008g, 0.02 mmol) was dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 110 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain compound 2 i. The isolated yield was 50%.
2i:1H NMR (400 MHz, CDCl3) δ 8.83 (dd, J = 4.1, 1.8 Hz, 1H), 8.34 (dd, J = 7.5, 1.4 Hz, 1H), 8.14 (dd, J = 8.4, 1.7 Hz, 1H), 7.59 (dd, J = 8.2, 1.3 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 7.41 (dd, J = 8.3, 4.1 Hz, 1H), 5.37 (dt, J = 10.1, 2.0 Hz, 1H), 3.60 (dd, J = 14.3, 1.9 Hz, 1H), 3.40 – 3.34 (m, 1H), 2.90 (dd, J = 14.3, 10.1 Hz, 1H), 2.75 – 2.65 (m, 1H), 2.20 – 2.12 (m, 2H), 2.09 (t, J = 7.2 Hz, 2H), 1.86 – 1.67 (m, 4H)..13C NMR (101 MHz, CDCl3) δ 169.18, 149.07, 140.12, 136.07, 132.77, 128.96, 126.81, 123.93, 121.50, 121.29, 96.70, 59.97, 57.06, 56.33, 35.95, 33.52, 29.02, 28.35, 18.44; HRMS Calcd for C19H20Cl3N2O [M+H]+: 397.0641, Found: 397.0638.
Example ten: synthesis of ethyl 2- (2-oxo-1- (8-quinolyl) -4- (2,2, 2-trichloroethyl) azetidinyl) acetate
Figure DEST_PATH_IMAGE012
Ethyl 3- (8-quinolinecarbonyl) -4-pentenoate 1j (0.060 g, 0.2 mmol), Cu (CH) was weighed3CN)4PF6(0.008g, 0.02 mmol) was dissolved in 2 mL of trichloromethylTo the alkane, DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 110 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction is finished, the crude product is purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain a compound 2 j. The isolated yield was 62%.
2j:1H NMR (400 MHz, CDCl3) δ 8.83 (dd, J = 4.1, 1.8 Hz, 1H), 8.30 (dd, J = 7.5, 1.4 Hz, 1H), 8.14 (dd, J = 8.4, 1.7 Hz, 1H), 7.60 (dd, J = 8.2, 1.3 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 7.41 (dd, J = 8.3, 4.1 Hz, 1H), 5.51 (dt, J = 9.9, 2.2 Hz, 1H), 4.19 – 4.12 (m, 2H), 3.78 – 3.73 (m, 1H), 3.69 (dd, J = 14.4, 2.0 Hz, 1H), 3.04 – 2.93 (m, 3H), 1.20 (t, J = 7.1 Hz, 3H).13C NMR (101 MHz, CDCl3)δ170.62, 167.09, 149.20, 140.21, 136.13, 132.53, 128.98, 126.79, 124.28, 121.63, 121.57, 96.40, 61.01, 59.83, 57.03, 53.51, 32.85, 14.08; HRMS Calcd for C18H17Cl3N2O3Na [M+Na]+: 437.0202, Found: 437.0201.
Example eleven: synthesis of 3- (1-chloropropyl) -4- (2,2, 2-trichloroethyl) -1- (8-quinolyl) -beta-lactam
Figure DEST_PATH_IMAGE013
Weighing N- (8-quinolyl) -2- (1-chloropropane) -3-butenamide 1k (0.058 g, 0.2 mmol), Cu (CH)3CN)4PF6(0.008g, 0.02 mmol) was dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 110 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain compound 2 k. The isolated yield was 48%.
2k:1H NMR (400 MHz, CDCl3) δ8.84 (dd, J = 4.1, 1.7 Hz, 1H), 8.32 (dd, J = 7.5, 1.2 Hz, 1H), 8.15 (dd, J = 8.4, 1.7 Hz, 1H), 7.61 (dd, J = 8.2, 1.2 Hz, 1H), 7.53 (t, J = 7.9 Hz, 1H), 5.38 (dt, J = 10.1, 2.0 Hz, 1H), 3.66 – 3.59 (m, 3H), 3.50 – 3.44 (m, 1H), 2.94 (dd, J = 14.4, 10.1 Hz, 1H), 2.27 – 2.16 (m, 2H), 2.12 – 2.00 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 168.50, 149.21, 140.16, 136.14, 132.54, 128.99, 126.79, 124.23, 121.60, 121.46, 96.52, 60.22, 56.89, 56.87, 44.75, 29.71, 26.36; HRMS Calcd for C17H17Cl4N2O [M+H]+: 321.1403, Found: 405.0087.
Example twelve: synthesis of 3, 3' -dimethyl-4- (2,2, 2-trichloroethyl) -1- (8-quinolyl) -beta-lactam
Figure DEST_PATH_IMAGE014
N- (8-quinolyl) -2, 2' -dimethyl-3-butenamide 1l (0.048 g, 0.2 mmol), Cu (CH) were weighed3CN)4PF6(0.008g, 0.02 mmol) was dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 110 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain 2l of the compound. The isolated yield was 43%.
2l: 1H NMR (400 MHz, CDCl3) δ 8.84 (dd, J = 4.2, 1.8 Hz, 1H), 8.13 (dd, J = 8.3, 1.7 Hz, 1H), 8.11 (dd, J = 7.5, 1.3 Hz, 1H), 7.65 (dd, J = 8.2, 1.3 Hz, 1H), 7.55 – 7.50 (m, 1H), 7.42 (dd, J = 8.3, 4.2 Hz, 1H), 5.32 (dd, J= 9.4, 1.5 Hz, 1H), 3.28 (dd, J = 15.1, 1.5 Hz, 1H), 3.15 (dd, J = 15.1, 9.4 Hz, 1H), 1.59 (s, 3H), 1.52 (s, 3H).13C NMR (101 MHz, CDCl3) δ 172.94, 149.41, 141.43, 136.02, 132.17, 129.03, 126.61, 125.05, 123.52, 121.60, 96.82, 65.61, 54.19, 52.55, 22.11, 18.76; HRMS Calcd for C16H15Cl3N2ONa [M+Na]+: 379.0148, Found: 379.0149.
Example thirteen: synthesis of 3-p-toluylethyl-4- (2,2, 2-trichloroethyl) -1- (8-quinolyl) beta-lactam
Figure DEST_PATH_IMAGE015
Weighing N- (8-quinolyl) -2-p-toluenethyl-3-butenamide 1m (0.063 g, 0.2 mmol), Cu (CH)3CN)4PF6(0.008g, 0.02 mmol) was dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 110 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain compound 2 m. The isolated yield was 52%.
2m: 1H NMR (400 MHz, CDCl3) δ 8.80 (dd, J = 4.1, 1.8 Hz, 1H), 8.28 (dd, J = 7.5, 1.3 Hz, 1H), 8.11 (dd, J = 8.3, 1.7 Hz, 1H), 7.58 (dd, J = 8.2, 1.3 Hz, 1H), 7.52 – 7.48 (m, 1H), 7.39 (dd, J = 8.3, 4.1 Hz, 1H), 7.25 (d, J= 7.6 Hz, 2H), 7.09 (d, J = 7.8 Hz, 2H), 5.39 (dt, J = 10.0, 2.0 Hz, 1H), 3.71 – 3.65 (m, 1H), 3.61 (dd, J = 14.4, 1.9 Hz, 1H), 3.33 – 3.20 (m, 2H), 2.94 (dd, J = 14.4, 10.1 Hz, 1H), 2.28 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 168.41, 149.09, 140.18, 136.06, 136.02, 134.81, 132.65, 129.34, 129.18, 128.94, 126.76, 124.12, 121.50, 121.46, 96.54, 59.48, 59.04, 56.88, 34.29, 21.07; HRMS Calcd for C22H19Cl3N2ONa[M+Na]+: 455.0461, Found: 455.0461.
Example fourteen: synthesis of 3-p-fluorophenethyl-4- (2,2, 2-trichloroethyl) -1- (8-quinolyl) beta-lactam
Figure DEST_PATH_IMAGE016
Weighing N- (8-quinolyl) -2-p-fluorophenethyl-3-butenamide 1N ((B))0.064 g, 0.2 mmol），Cu(CH3CN)4PF6(0.008g, 0.02 mmol) was dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 110 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain compound 2 n. The isolated yield was 61%.
2n: 1H NMR (400 MHz, CDCl3) δ 8.78 (dd, J = 4.1, 1.7 Hz, 1H), 8.26 (dd, J = 7.5, 1.2 Hz, 1H), 8.12 (dd, J = 8.3, 1.7 Hz, 1H), 7.59 (dd, J = 8.1, 1.1 Hz, 1H), 7.50 (t, J = 7.9 Hz, 1H), 7.40 (dd, J = 8.3, 4.1 Hz, 1H), 7.34 – 7.30 (m, 2H), 7.00 – 6.93 (m, 2H), 5.38 (dt, J = 10.1, 2.0 Hz, 1H), 3.70 – 3.65 (m, 1H), 3.59 (dd, J = 14.4, 1.9 Hz, 1H), 3.32 (dd, J = 14.3, 5.0 Hz, 1H), 3.23 (dd, J = 14.3, 7.6 Hz, 1H), 2.95 (dd, J = 14.4, 10.2 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 168.08 , 161.77 (d, J = 244.3 Hz),149.14, 140.17, 136.05, 133.52, 133.49, 132.42, 131.05, 130.97, 128.95, 126.73, 124.28, 121.55, 121.50, 115.40, 115.19, 96.52, 59.16, 58.81, 56.74, 33.73. 19F NMR (377 MHz, CDCl3) δ -116.53 (s); HRMS Calcd for C21H17Cl3FN2O[M+H]+: 437.0390, Found: 437.0388.
Example fifteen: synthesis of 1- (8-quinolyl) -4- (2- (1,1, 1-trichloropropyl)) azetidin-2-one
Figure DEST_PATH_IMAGE017
N- (8-quinolyl) -3-pentenamide 1o (0.045 g, 0.2 mmol), Cu (CH) were weighed3CN)4PF6(0.008g, 0.02 mmol) was dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 110 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction is finished, the crude product is chromatographically separated by a silica gel column (petroleum ether: B)Ethyl acid = 30: 1) to yield compound 2o after purification. The isolated yield was 41%.
2o: 1H NMR (400 MHz, CDCl3) δ 8.89 (dd, J = 4.2, 1.7 Hz, 1H), 8.15 (dd, J = 8.3, 1.7 Hz, 1H), 7.89 (dd, J = 7.4, 1.3 Hz, 1H), 7.68 (dd, J = 8.2, 1.2 Hz, 1H), 7.59 – 7.50 (m, 1H), 7.43 (dd, J = 8.3, 4.2 Hz, 1H), 5.80 (ddd, J = 6.7, 5.6, 2.6 Hz, 1H), 3.64 (dd, J = 15.5, 5.5 Hz, 1H), 3.27 (dd, J = 15.5, 2.6 Hz, 1H), 3.08 (p, J = 6.8 Hz, 1H), 1.22 (d, J = 6.8 Hz, 3H).13C NMR (101 MHz, CDCl3) δ 166.29 (s), 148.92 (s), 140.72 (s), 140.58 (s), 137.37 (s), 136.09 (s), 133.51 (s), 130.38 (s), 128.99 (s), 126.73 (s), 124.08 (s), 121.62 (s), 121.37 (s), 91.01 (s), 55.89 (s), 43.04 (s), 34.93 (s), 31.09 (s); HRMS Calcd for C15H14Cl3N2O [M+H]+: 343.0172, found: 343.0168.
Example sixteen: synthesis of 1- (8-quinolyl) -4- (2- (1,1, 1-trichlorobutyl)) azetidin-2-one
Figure DEST_PATH_IMAGE018
Weighing N- (8-quinolyl) -3-hexenylamide 1p (0.048 g, 0.2 mmol), Cu (CH)3CN)4PF6(0.008g, 0.02 mmol) was dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 110 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain compound 2 p. The isolated yield was 33%.
2p: 1H NMR (400 MHz, CDCl3) δ 8.85 (dd, J = 4.2, 1.7 Hz, 1H), 8.16 (dd, J = 8.3, 1.7 Hz, 1H), 8.01 (dd, J = 7.5, 1.3 Hz, 1H), 7.66 (dd, J = 8.2, 1.2 Hz, 1H), 7.57 – 7.52 (m, 1H), 7.43 (dd, J = 8.3, 4.2 Hz, 1H), 5.83 (dd, J= 8.6, 4.8 Hz, 1H), 3.55 – 3.50 (m, 2H), 2.94 – 2.88 (m, 1H), 1.68 – 1.53 (m, 2H), 1.13 (t, J = 7.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 166.62, 149.19, 141.95, 136.24, 133.22, 129.10, 126.65, 125.24, 123.97, 121.51, 102.53, 62.31, 57.22, 42.94, 24.11, 14.02; HRMS Calcd for C16H16Cl3N2O [M+H]+: 357.0328, found:357.0320.
Example seventeen: synthesis of 1- (8-quinolyl) -4- (1,1, 1-trichloro-3-phenyl-2-propyl) azetidin-2-one
Figure DEST_PATH_IMAGE019
Weighing N- (8-quinolyl) -5-phenyl-3-hexenamide 1q (0.048 g, 0.2 mmol), Cu (CH)3CN)4PF6(0.008g, 0.02 mmol) was dissolved in 2 mL of chloroform, and DTBP (0.176 g, 1.2 mmol) was added. The mixture was heated to 110 ℃ for reaction and the reaction was followed by TLC until the reaction was complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain compound 2 q. The isolated yield was 21%.
2q: 1H NMR (400 MHz, CDCl3) δ 8.18 (dd, J = 4.2, 1.8 Hz, 1H), 8.08 (dd, J = 8.3, 1.7 Hz, 1H), 7.89 (dd, J = 7.5, 1.3 Hz, 1H), 7.58 (dd, J = 8.2, 1.3 Hz, 1H), 7.49 – 7.42 (m, 1H), 7.37 – 7.27 (m, 4H), 7.24 – 7.19 (m, 2H), 5.83 (dt, J = 6.4, 3.3 Hz, 1H), 3.61 – 3.53 (m, 2H), 3.49 – 3.38 (m, 2H), 2.84 (dd, J = 14.7, 9.2 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ166.04, 148.90, 141.45, 138.55, 135.98, 133.23, 128.98, 128.84, 128.71, 126.77, 126.59, 124.76, 123.33, 121.23, 102.07, 60.87, 56.80, 41.27, 36.48; HRMS Calcd for C21H18Cl3N2O [M+H]+: 393.1191, Found: 393.1198.
In summary, the present invention discloses a method for preparing 4- (2,2, 2-trichloroethyl) -1- (8-quinolyl) -beta-lactam derivatives, which is characterized in that: dissolving copper salts such as substituted N-quinoline-3-butenamide derivatives, di-tert-butyl peroxide, copper tetranitrile hexafluorophosphate and the like in trichloromethane, reacting at 110 ℃, and preparing a plurality of 4- (2,2, 2-trichloroethyl) -beta-lactam derivatives with high yield.
The above is only a preferred embodiment of the present invention, and is not intended to limit the present invention, it should be noted that, for those skilled in the art, many modifications and variations can be made without departing from the technical principle of the present invention, and these modifications and variations should also be regarded as the protection scope of the present invention.

Claims (9)

1. A method for preparing 4- (2,2, 2-trichloroethyl) -beta-lactam derivatives, which is characterized by comprising the following steps: reacting the substituted N-quinoline-3-butenamide derivative shown in the formula (1) in chloroform at 100-120 ℃ under the action of an oxidant and a copper salt catalyst, and obtaining a 4- (2,2, 2-trichloroethyl) -beta-lactam derivative shown in the formula (2) after the reaction is completed;
Figure 758862DEST_PATH_IMAGE001
；
wherein R is1Hydrogen, C1-C6 alkyl, phenyl or substituted phenyl;
R2and R3Independently selected from hydrogen, C1-C6 alkyl, phenyl, substituted phenyl or C1-C6 unsaturated alkyl;
the substituent on the substituted phenyl is C1-C6 alkyl or halogen.
2. The method of claim 1, wherein: the C1-C6 alkyl comprises one of substituted or unsubstituted straight-chain alkyl, substituted or unsubstituted branched-chain alkyl and substituted or unsubstituted cycloalkyl; wherein, the substituent groups on the substituted straight-chain alkyl, the substituted branched-chain alkyl and the substituted naphthenic base are respectively and independently selected from one or more of alkyl, halogen and ester group.
3. According to the rightThe method according to claim 1, wherein: r1Is hydrogen, R3Is hydrogen or methyl, R2The alkyl group is hydrogen, unsubstituted C1-C6 linear alkyl, ester group substituted C1-C6 alkyl, allyl, benzyl, phenethyl, cyclopropylmethyl, cyclobutylmethyl, halopropyl, p-tolylethyl or halophenethyl.
4. The method of claim 1, wherein: r2Is hydrogen, R3Is hydrogen, R1Is C1-C6 alkyl or benzyl.
5. The method of claim 1, wherein: the oxidant is di-tert-butyl peroxide.
6. The method of claim 1, wherein: the copper salt catalyst is one or more of cuprous bromide, copper acetate, cuprous chloride, tetraethyl nitrile copper hexafluorophosphate, copper trifluoromethanesulfonate and copper bromide.
7. The method of claim 1, wherein: the molar ratio of the substituted N-quinoline-3-butenamide derivative to the trichloromethane to the oxidant to the copper salt catalyst is 1: 8-12: 3-8: 0.05 to 0.2.
8. The method of claim 1, wherein: the molar ratio of the substituted N-quinoline-3-butenamide derivative to the trichloromethane to the oxidant to the copper salt catalyst is 1:10:6: 0.1.
9. The method of claim 1, wherein: the reaction temperature was 110 ℃.
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