Preparation method of 2-(4, 4-dichloro-1-(8-quinolyl)-2-azacyclobutyl) carboxylic ester derivative

A technology based on azetidinyl and quinoline, applied in the field of preparation of organic compounds, can solve the problems of harsh reaction conditions, low technical yield, unfriendly environment, etc., and achieve easy-to-obtain raw materials, simple operation and post-treatment process , the effect of high yield

Active Publication Date: 2021-06-29
SUZHOU UNIV
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Problems solved by technology

But these methods all can not realize the synthesis of 2-(4,4-dichloro-1-(8-quinolyl)-2-azetidinyl) carboxylate derivatives, and the relative preparation technology yield is relatively low Low, using expensive raw materials, harsh reaction conditions and unfriendly to the environment

Method used

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  • Preparation method of 2-(4, 4-dichloro-1-(8-quinolyl)-2-azacyclobutyl) carboxylic ester derivative
  • Preparation method of 2-(4, 4-dichloro-1-(8-quinolyl)-2-azacyclobutyl) carboxylic ester derivative
  • Preparation method of 2-(4, 4-dichloro-1-(8-quinolyl)-2-azacyclobutyl) carboxylic ester derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Example 1: Synthesis of 2-(4,4-dichloro-1-(8-quinolyl)-2-azetidinyl)methyl acetate

[0022]

[0023] Weigh 4-(2,2,2-trichloroethyl)-1-(8-quinolyl)-β-lactam 1a (0.066g, 0.2mmol), dissolve in sodium methoxide (0.016g, 0.03mmol) In 2mL methanol. The mixture was heated to 90°C for reaction, followed by TLC until the reaction was completely completed. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=20:1) to obtain compound 2a. Isolated yield was 72%.

[0024] 2a: 1H NMR (400MHz, CDCl3) δ8.73 (d, J = 2.9Hz, 1H), 8.07 (d, J = 7.9Hz, 1H), 7.46–7.34 (m, 2H), 7.13 (d, J = 8.1Hz, 1H), 6.74(d, J=7.6Hz, 1H), 6.63(d, J=8.1Hz, 1H), 5.98(d, J=8.7Hz, 1H), 4.93–4.74(m, 1H) ,3.74(s,3H),2.95–2.79(m,2H).13C NMR(101MHz,CDCl3)δ170.84,147.26,142.75,138.36,136.05,131.15,128.65,127.64,122.98,121.52,115.016,106.05. 49.68, 38.94; HRMS (ESI-TOF) Calcd for C15H15Cl2N2O2[M+H]+: 325.0511, found: 325.0527.

Embodiment 2

[0025] Example 2: Synthesis of 2-(4,4-dichloro-1-(8-quinolyl)-2-azetidinyl)propionic acid methyl ester

[0026]

[0027] Weigh 3-methyl 4-(2,2,2-trichloroethyl)-1-(8-quinolyl)-β-lactam 1b (0.069g, 0.2mmol), sodium methoxide (0.016g, 0.03mmol) was dissolved in 2mL methanol. The mixture was heated to 90°C for reaction, followed by TLC until the reaction was completely completed. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=20:1) to obtain compound 2b. Isolated yield was 72%.

[0028] 2b: 1H NMR (400MHz, CDCl3) δ8.72 (dd, J = 8.9, 3.6Hz, 1H), 8.06 (d, J = 8.2Hz, 1H), 7.43–7.34 (m, 2H), 7.09 (dd, J=17.9,8.2Hz,1H),6.84–6.53(m,2H),5.90(dd,J=36.9,9.3Hz,1H),4.71–4.28(m,1H),3.71(t,J=20.0Hz ,3H),3.25–2.88(m,1H),1.41–1.34(m,3H); HRMS(ESI-TOF) Calcd for C16H16Cl2N2O2Na[M+Na]+:361.0487,found:361.0491.

Embodiment 3

[0029] Example 3: Synthesis of 2-(4,4-dichloro-1-(8-quinolyl)-2-azetidinyl)butanoic acid methyl ester

[0030]

[0031] Weigh 3-ethyl 4-(2,2,2-trichloroethyl)-1-(8-quinolyl)-β-lactam 1c (0.071g, 0.2mmol), sodium methoxide (0.016g, 0.03mmol) was dissolved in 2mL methanol. The mixture was heated to 90°C for reaction, followed by TLC until the reaction was completely completed. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=20:1) to obtain compound 2c. Isolated yield was 70%.

[0032] 2c:1H NMR (400MHz, CDCl3) δ8.76–8.68(m,1H),8.09–8.03(m,1H),7.43–7.33(m,2H),7.14–7.04(m,1H),6.85–6.46 (m,2H),5.88(dd,J=50.9,9.3Hz,1H),4.70–4.27(m,1H),3.73(t,J=15.9Hz,3H),3.20–2.70(m,1H), 1.98–1.69(m,2H),1.05–0.96(m,3H); HRMS(ESI-TOF) Calcd for C17H19Cl2N2O2[M+H]+:353.0824,found:353.0825.

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Abstract

The invention relates to a preparation method of a 2-(4, 4-dichloro-1-(8-quinolyl)-2-azacyclobutyl) carboxylic ester derivative, which comprises the following steps of reacting a substituted 4-(2, 2, 2-trichloroethyl)-1-(8-quinolyl)-beta-lactam derivative, a nucleophilic reagent sodium alkoxide and a monohydric alcohol solvent at 80-110 DEG C to obtain the 2-(4, 4-dichloro-1-(8-quinolyl)-2-azacyclobutyl) carboxylic ester derivative. The raw materials are easy to obtain, environmentally friendly and various in variety, the obtained products are various in type, can be directly used and can also be used for other further reactions, the reaction conditions are mild, the process is simple, the yield is high, and the method is suitable for large-scale production.

Description

technical field [0001] The invention relates to the technical field of preparation of organic compounds, in particular to a 2-(4,4-dichloro-1-(8-quinolyl)-2-azetidinyl) carboxylate derivative method of preparation. Background technique [0002] Azetidine is an important component of nitrogen-containing heterocycles, and is the core skeleton of many natural products and drug molecules, with significant biological activity. Therefore, the synthesis of azetidine derivatives is of great value. [0003] So far, the synthetic methods of azetidine derivatives mainly contain the following types: [0004] The synthesis method of azetidine derivatives is disclosed in Chemistry Letters, 1988, 17, 1065-1068, and the method is ring-closed by direct nucleophilic substitution reaction; Org. Lett., 2010, 12, 5044-5047 discloses A cyclization reaction of butene amine iodine to prepare azetidine derivatives; Inorganic Chemistry Communications, 2012, 20, 234-237 realized the use of LiAlH 4...

Claims

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Application Information

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IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 曾润生张科甘紫旭赵应声
Owner SUZHOU UNIV
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