阅读说明：本技术 一种4-氯喹啉类化合物的合成方法 (Synthesis method of 4-chloroquinoline compound ) 是由 黄鹏 尹磊 孙琪 范宇馨 于 2021-10-23 设计创作，主要内容包括：本发明公开一种4-氯喹啉类化合物的合成方法。属于有机合成技术领域。在室温下,将三光气溶于有机溶剂中,加入N,S-缩烯酮类化合物,将反应体系密封后加热至90～140℃,继续搅拌反应2～5h,所得反应液经后处理得4-氯喹啉类化合物。通过本发明方法合成4-氯喹啉类化合物,步骤少,产率高,操作安全便捷。(The invention discloses a synthesis method of a 4-chloroquinoline compound. Belongs to the technical field of organic synthesis. At room temperature, dissolving triphosgene in an organic solvent, adding an N, S-ketene acetal compound, sealing a reaction system, heating to 90-140 ℃, continuously stirring for reaction for 2-5 hours, and carrying out aftertreatment on the obtained reaction liquid to obtain the 4-chloroquinoline compound. The method for synthesizing the 4-chloroquinoline compound has the advantages of few steps, high yield, and safe and convenient operation.)

1. a method for synthesizing a 4-chloroquinoline compound is characterized by comprising the following steps: at room temperature, dissolving triphosgene in an organic solvent, adding an N, S-ketene acetal compound, sealing a reaction system, heating to 90-140 ℃, continuously stirring for reaction for 2-5 hours, and carrying out aftertreatment on the obtained reaction liquid to obtain the 4-chloroquinoline compound.

2. The method for synthesizing 4-chloroquinoline compounds according to claim 1, wherein the N, S-ketene acetals have the structural formula (I):

wherein R is¹、R²、R³And R⁴Each independently selected from hydrogen and C₁～C₄Alkyl radical, C₁～C₄Alkoxy radical, C₁～C₄Alkylthio, halogen, dimethylamino, nitro or trifluoromethyl; r⁵、R⁶Each independently selected from methyl, ethyl, isopropyl, tert-butyl, benzyl, allyl.

3. The method for synthesizing 4-chloroquinoline compounds according to claim 1, wherein the organic solvent is one or a mixture of two or more selected from benzene, toluene, xylene, chlorobenzene and 1, 2-dichloroethane.

4. The method for synthesizing 4-chloroquinoline compounds according to claim 1, wherein the amount of the organic solvent is 2-10 mL per 1mmol of N, S-ketene acetal compound.

5. The method for synthesizing 4-chloroquinoline compounds according to claim 1, wherein the N, S-ketene acetal compound is triphosgene (1-2) according to the mass ratio.

6. The method for synthesizing 4-chloroquinoline compounds according to claim 1, wherein the post-treatment method comprises the following steps: concentrating the obtained reaction solution under reduced pressure, separating the obtained concentrate by silica gel column chromatography, collecting eluent by using mixed solution of petroleum ether and ethyl acetate as eluent, evaporating the solvent and drying.

7. The method for synthesizing a 4-chloroquinoline compound according to claim 6, wherein the petroleum ether and the ethyl acetate are (50-100): 1 in volume ratio.

8. A 4-chloroquinoline synthesized according to the method of any one of claims 1 to 7, wherein the 4-chloroquinoline has the formula of formula (ii):

wherein R is¹、R²、R³And R⁴Each independently selected from hydrogen and C₁～C₄Alkyl radical, C₁～C₄Alkoxy radical, C₁～C₄Alkylthio, halogen, dimethylamino, nitro or trifluoromethyl; r⁵、R⁶Each independently selected from methyl, ethyl, isopropyl, tert-butyl, benzyl, allyl.

Technical Field

The invention relates to a 4-chloroquinoline compound and a synthesis method thereof, belonging to the technical field of organic synthesis.

Background

The 4-chloroquinoline compounds belong to a class of quinoline derivatives and are widely used as raw materials or intermediates for synthesizing quinoline pharmaceutically active molecules (ACS Omega 2021,6,12984-12994), catalysts (Angew. chem. int. Ed.2020,59, 2735-2739), organic luminescent materials (chem. Commun.2015,51,15241-15244) and the like.

The currently common method for synthesizing 4-chloroquinoline compounds is to construct 4-hydroxyquinoline intermediate in advance through condensation reaction, and then to synthesize the intermediate in POCl₃Is converted into 4-chloroquinoline compounds under the action (i.e. J.Med.chem.2020,63, 11756-. The process is classically reliable, but requires the use of high-boiling organic solvents (>200 ℃) and a strongly corrosive POCl₃As a chlorinating agent, at least three steps are required from raw materials to products, the reaction time and the steps are long, and the products areThe total yield of the method is about 50 percent, the total yield is low, and a large amount of phosphoric acid waste is generated. There are also reports on methods for synthesizing 4-chloroquinoline compounds in one step by using various functionalized arylamines as raw materials (i.e., (Synthesis 2015,47, 3139-.

Disclosure of Invention

Aiming at the defects in the prior art, the invention provides a method for synthesizing a 4-chloroquinoline compound from simple and easily-obtained raw materials in one step. The method has the advantages of few synthesis steps, mild reaction conditions, safe and convenient operation, low production cost, high yield and wide application range.

The technical scheme adopted by the invention is as follows: a method for synthesizing a 4-chloroquinoline compound comprises the following steps: at room temperature, dissolving triphosgene (BTC) in an organic solvent, adding an N, S-ketene acetal compound, sealing a reaction system, heating to 90-140 ℃, continuously stirring for reaction for 2-5 hours, and carrying out aftertreatment on the obtained reaction liquid to obtain the 4-chloroquinoline compound.

The N, S-ketene acetal compound has a structural formula shown in a formula (I):

wherein R is¹、R²、R³And R⁴Each independently selected from hydrogen and C₁～C₄Alkyl radical, C₁～C₄Alkoxy radical, C₁～C₄Alkylthio, halogen, dimethylamino, nitro or trifluoromethyl; r⁵、R⁶Each independently selected from methyl, ethyl, isopropyl, tert-butyl, benzyl, allyl.

In the synthesis method of the 4-chloroquinoline compound, the organic solvent is one or a mixture of two or more of benzene, toluene, xylene, chlorobenzene and 1, 2-dichloroethane.

According to the synthesis method of the 4-chloroquinoline compound, the amount of the organic solvent is 2-10 mL per 1mmol of the N, S-ketene acetal compound.

The synthesis method of the 4-chloroquinoline compound comprises the following steps of (1-2) according to the mass ratio, wherein triphosgene is an N, S-ketene acetal compound.

The synthesis method of the 4-chloroquinoline compound comprises the following steps: and concentrating the obtained reaction solution under reduced pressure, carrying out silica gel column chromatography separation on the obtained concentrate, collecting eluent by using a mixed solution of petroleum ether and ethyl acetate with the volume ratio of (50-100): 1 as an eluent, evaporating the solvent, and drying.

The 4-chloroquinoline compound synthesized by the method has a structural formula shown in a general formula (II):

wherein R is¹、R²、R³And R⁴Each independently selected from hydrogen and C₁～C₄Alkyl radical, C₁～C₄Alkoxy radical, C₁～C₄Alkylthio, halogen, dimethylamino, nitro or trifluoromethyl; r⁵、R⁶Each independently selected from methyl, ethyl, isopropyl, tert-butyl, benzyl, allyl.

The reaction formula of the invention is as follows:

the invention has the beneficial effects that:

(1) the invention shortens the synthesis reaction time and steps of the 4-chloroquinoline compound.

(2) The N, S-ketene acetal compound (I) used as the raw material is easy to prepare and has low cost.

(3) The triphosgene used in the invention is solid, is safer and more convenient to operate, is a bulk chemical product and has low price.

Detailed Description

The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.

EXAMPLE 12 Synthesis of methyl ethylthio-4-chloroquinoline-3-carboxylate

Adding 13mL of chlorobenzene and 0.594g of BTC (2.0mmol) into a 15mL thick-wall pressure-resistant bottle provided with a magnetic stirrer at room temperature, dissolving the chlorobenzene and the BTC at room temperature, adding 0.590g of a substrate 1a (2.0mmol) into the chlorobenzene, sealing a reaction system, heating the reaction system to 120 ℃, continuing to perform magnetic stirring reaction for 2.5 hours, concentrating the reaction solution under reduced pressure after the reaction is finished, and performing silica gel column chromatography separation on the obtained concentrate, wherein the volume ratio of petroleum ether to ethyl acetate is 50: 1 as eluent, collecting the eluent containing the target product, evaporating the solvent and drying to obtain 0.506g of a light yellow solid product 2-ethylthio-4-chloroquinoline-3-methyl formate 2a with the yield of 90%.

The above reaction formula is as follows:

preparation of product 2-ethylsulfanyl-4-chloroquinoline-3-carboxylic acid methyl ester 2a¹H NMR and¹³the C NMR data are as follows:

¹H NMR(300MHz,CDCl₃):δ＝1.43(t,J＝7.4Hz,3H),3.38(q,J＝7.4Hz,2H),4.04(s,3H),7.55(t,J＝8.1Hz,1H),7.74(t,J＝7.8Hz,1H),7.96(d,J＝8.4Hz,1H),8.15(d,J＝8.6Hz,1H)；¹³C NMR(75MHz,CDCl₃):δ＝14.1,24.9,53.0,122.9,124.4,126.0,126.3,128.1,131.2,139.0,148.0,155.9,165.4。

EXAMPLE 26 Synthesis of methyl-2-ethylsulfanyl-4-chloroquinoline-3-carboxylate

Adding 14mL of toluene and 0.594g of BTC (2.0mmol) into a 38mL thick-wall pressure-resistant bottle provided with a magnetic stirrer at room temperature, dissolving the toluene and the BTC at room temperature, adding 0.618g N, S-ketene acetal 1b (2.0mmol) into the bottle, sealing a reaction system, heating the reaction system to 120 ℃, continuing to perform magnetic stirring reaction for 3 hours, after the reaction is finished, concentrating the reaction solution under reduced pressure, and performing silica gel column chromatography separation on the obtained concentrate, wherein the volume ratio of petroleum ether to ethyl acetate is 50: 1 as an eluent, and collecting the eluate containing the desired product, evaporating the solvent and drying to obtain 0.473g of methyl 6-methyl-2-ethylsulfanyl-4-chloroquinoline-3-carboxylate 2b as a white solid in a yield of 80%.

The above reaction formula is as follows:

preparation of product 6-methyl-2-ethylsulfanyl-4-chloroquinoline-3-carboxylic acid methyl ester 2b¹H NMR and¹³the C NMR data are as follows:

¹H NMR(300MHz,CDCl₃):δ＝1.42(t,J＝7.4Hz,3H),2.54(s,3H),3.36(q,J＝7.3Hz,2H),4.03(s,3H),7.56(dd,J＝8.5,1.8Hz,1H),7.93–7.82(m,2H)；¹³C NMR(75MHz,CDCl₃):δ＝14.2,21.6,25.0,52.9,122.8,123.3,126.0,127.9,133.4,136.7,138.5,146.6,154.7,165.6。

EXAMPLE 36 Synthesis of methyl (methylthio) -2-ethylthio-4-chloroquinoline-3-carboxylate

Adding 10mL of dimethylbenzene and 0.712g of BTC (2.4mmol) into a 15mL thick-walled pressure-resistant bottle with a magnetic stirrer at room temperature, dissolving the dimethylbenzene and the BTC at room temperature, adding 0.682g N and S-ketene acetal 1c (2.0mmol), sealing a reaction system, heating to 120 ℃, continuing to perform magnetic stirring reaction for 3 hours, concentrating the reaction solution under reduced pressure after the reaction is finished, and performing silica gel column chromatography separation on the obtained concentrate, wherein the volume ratio of petroleum ether to ethyl acetate is 70: 1 as an eluent, and collecting the eluate containing the objective product, evaporating the solvent and drying to obtain 0.577g of a yellow solid product, methyl 6-methylsulfanyl-2-ethylsulfanyl-4-chloroquinoline-3-carboxylate 2c, in 88% yield.

The above reaction formula is as follows:

preparation of product 6-methylsulfanyl-2-ethylsulfanyl-4-chloroquinoline-3-carboxylic acid methyl ester 2c¹H NMR and¹³the C NMR data are as follows:

¹H NMR(300MHz,CDCl₃):δ＝1.41(t,J＝7.4Hz,3H),2.61(s,3H),3.35(q,J＝7.4Hz,2H),4.04(s,3H),7.59(dd,J＝8.8,2.2Hz,1H),7.89–7.79(m,2H)；¹³C NMR(75MHz,CDCl₃):δ＝14.0,15.2,24.9,52.9,118.5,123.2,126.2,128.2,130.2,137.5,138.0,146.0,165.3。

EXAMPLE 46 Synthesis of methyl methoxy-2-ethylsulfanyl-4-chloroquinoline-3-carboxylate

Adding 10mL of 1, 2-dichloroethane and 0.652g of BTC (2.2mmol) into a 38mL thick-wall pressure-resistant bottle provided with a magnetic stirrer at room temperature, dissolving the 1, 2.2mmol of 1, 652g of BTC at room temperature, adding 0.650g N, S-ketene acetal 1d (2.0mmol), sealing the reaction system, heating to 100 ℃, continuing the magnetic stirring reaction for 4 hours, after the reaction is finished, concentrating the reaction solution under reduced pressure, and separating the obtained concentrate by silica gel column chromatography, wherein the volume ratio of petroleum ether to ethyl acetate is 60: 1 as eluent, collecting the eluent containing the target product, evaporating the solvent and drying to obtain 0.530g of a white solid product, namely 6-methoxy-2-ethylthio-4-chloroquinoline-3-methyl formate 2d, with the yield of 85%.

The above reaction formula is as follows:

preparation of product 6-methoxy-2-ethylsulfanyl-4-chloroquinoline-3-carboxylic acid methyl ester 2d¹H NMR and¹³the C NMR data are as follows:

¹H NMR(300MHz,CDCl₃):δ＝1.41(t,J＝7.3Hz,3H),3.34(q,J＝7.4Hz,2H),3.95(s,3H),4.04(s,3H),7.42–7.32(m,2H),7.90–7.81(m,1H)；¹³C NMR(75MHz,CDCl₃):δ＝14.1,24.9,52.8,55.4,102.1,123.5,126.1,129.7,137.5,144.0,152.6,157.8,165.5。

EXAMPLE 56 Synthesis of methyl fluoro-2-ethylsulfanyl-4-chloroquinoline-3-carboxylate

Adding 16mL of chlorobenzene and 0.594g of BTC (2.0mmol) into a 38mL thick-wall pressure-resistant bottle provided with a magnetic stirrer at room temperature, dissolving the chlorobenzene and the BTC at room temperature, adding 0.626g N, S-ketene acetal 1e (2.0mmol), sealing a reaction system, heating to 120 ℃, continuing to carry out magnetic stirring reaction for 3 hours, concentrating the reaction solution under reduced pressure after the reaction is finished, and carrying out silica gel column chromatography separation on the obtained concentrate, wherein the volume ratio of petroleum ether to ethyl acetate is 90: 1 as eluent, collecting the eluent containing the target product, evaporating the solvent and drying to obtain 0.484 white solid product 6-fluoro-2-ethylsulfanyl-4-chloroquinoline-3-methyl formate 2e with a yield of 81%.

The above reaction formula is as follows:

preparation of product 6-fluoro-2-ethylsulfanyl-4-chloroquinoline-3-carboxylic acid methyl ester 2e¹H NMR and¹³the C NMR data are as follows:

¹H NMR(300MHz,CDCl₃):δ＝1.42(t,J＝7.4Hz,3H),3.35(q,J＝7.3Hz,2H),4.04(s,3H),7.50(td,J＝8.7,3.0Hz,1H),7.78(dd,J＝9.2,2.8Hz,1H),7.96(dd,J＝9.2,5.2Hz,1H)；¹³C NMR(75MHz,CDCl₃):δ＝14.0,24.9,53.1,108.3,108.6,121.0,121.3,123.7,123.9,126.6,130.6,130.8,138.1,138.2,145.0,155.4,158.8,162.1,165.2。

EXAMPLE 66 Synthesis of methyl nitro-2-ethylsulfanyl-4-chloroquinoline-3-carboxylate

Adding 17mL of chlorobenzene and 0.594g of BTC (2.0mmol) into a 38mL thick-wall pressure-resistant bottle provided with a magnetic stirrer at room temperature, dissolving the chlorobenzene and the BTC at room temperature, adding 0.652g N and S-ketene acetal 1f (2.0mmol), heating a reaction system to 120 ℃, continuing to perform magnetic stirring reaction for 5 hours, after the reaction is finished, concentrating the reaction solution under reduced pressure, and performing silica gel column chromatography on the obtained concentrate, wherein the volume ratio of petroleum ether to ethyl acetate is 100: 1 as eluent, collecting the eluent containing the target product, evaporating the solvent and drying to obtain 0.333 pale yellow solid product 6-nitro-2-ethylthio-4-chloroquinoline-3-methyl formate 2f with the yield of 51%.

The above reaction formula is as follows:

preparation of product 6-nitro-2-ethylsulfanyl-4-chloroquinoline-3-carboxylic acid methyl ester 2f¹H NMR and¹³the C NMR data are as follows:

¹H NMR(300MHz,CDCl₃):δ＝1.40(t,J＝7.41Hz,3H),3.38(q,J＝7.4Hz,2H),4.06(s,3H),8.03(dq,J＝9.1,0.6Hz,1H),8.54–8.43(m,1H),9.08(d,J＝2.5Hz,1H)；¹³C NMR(75MHz,CDCl₃):δ＝13.8,25.2,53.3,121.7,122.3,124.9,127.6,129.8,140.1,145.1,149.7,161.5,164.5。

EXAMPLE synthesis of methyl 78-methoxy-2-ethylsulfanyl-4-chloroquinoline-3-carboxylate

Adding 10mL of chlorobenzene and 0.594g of BTC (2.0mmol) into a 38mL thick-wall pressure-resistant bottle provided with a magnetic stirrer at room temperature, dissolving the chlorobenzene and the BTC at room temperature, adding 0.650g N and 1g of S-ketene acetal (2.0mmol), sealing a reaction system, heating to 120 ℃, continuing to perform magnetic stirring reaction for 4 hours, after the reaction is finished, concentrating the reaction solution under reduced pressure, and performing silica gel column chromatography separation on the obtained concentrate, wherein the volume ratio of petroleum ether to ethyl acetate is 50: 1 as eluent, collecting the eluent containing the target product, evaporating off the solvent and drying to obtain 0.330g of white solid product 8-methoxy-2-ethylthio-4-chloroquinoline-3-methyl formate 2g with a yield of 53%.

The above reaction formula is as follows:

preparation of product methyl 8-methoxy-2-ethylsulfanyl-4-chloroquinoline-3-carboxylate 2g¹H NMR and¹³the C NMR data are as follows:

¹H NMR(300MHz,CDCl₃):δ＝1.44(t,J＝7.4Hz,3H),3.42(q,J＝7.4Hz,2H),4.05(d,J＝2.8Hz,6H),7.12(dd,J＝7.9,1.2Hz,1H),7.46(dd,J＝8.5,7.8Hz,1H),7.73(dd,J＝8.5,1.2Hz,1H)；¹³C NMR(75MHz,CDCl₃):δ＝13.8,25.2,52.9,56.4,110.4,116.1,124.0,126.6,139.0,139.9,154.4,154.7,165.5。

example Synthesis of methyl 88-methyl-2-ethylsulfanyl-4-chloroquinoline-3-carboxylate

At room temperature, adding 10mL of toluene and 0.594g of BTC (2.0mmol) into a 38mL thick-walled pressure-resistant bottle provided with a magnetic stirrer, dissolving the toluene and the BTC at room temperature, adding 0.618g N and S-ketene acetal for 1h (2.0mmol), heating a reaction system to 110 ℃, continuing to perform magnetic stirring reaction for 4h, after the reaction is finished, concentrating the reaction solution under reduced pressure, and performing silica gel column chromatography on the obtained concentrate, wherein the volume ratio of petroleum ether to ethyl acetate is 70: 1 as eluent, collecting the eluent containing the target product, evaporating the solvent and drying to obtain 0.390g of a light yellow solid product, namely 8-methyl-2-ethylthio-4-chloroquinoline-3-methyl formate, for 2h, wherein the yield is 66%.

The above reaction formula is as follows:

preparation of product 8-methyl-2-ethylsulfanyl-4-chloroquinoline-3-carboxylic acid methyl ester 2h¹H NMR and¹³the C NMR data are as follows:

¹H NMR(300MHz,CDCl₃):δ＝1.46(t,J＝7.3Hz,3H),2.74(s,3H),3.36(q,J＝7.3Hz,2H),4.03(s,3H),7.49–7.36(m,1H),7.58(d,J＝7.1Hz,1H),8.00(d,J＝8.4Hz,1H)；¹³C NMR(75MHz,CDCl₃):δ＝14.0,17.8,25.1,52.9,122.3,122.7,125.5,126.1,131.5,136.2,139.3,146.8,154.5,165.6。

EXAMPLE synthesis of methyl 92-benzylthio-4-chloroquinoline-3-carboxylate

Adding 10mL of chlorobenzene and 0.594g of BTC (2.0mmol) into a 38mL thick-wall pressure-resistant bottle provided with a magnetic stirrer at room temperature, dissolving the chlorobenzene and the BTC at room temperature, adding 0.714g N, S-ketene acetal 1i (2.0mmol), sealing a reaction system, heating to 120 ℃, continuing to perform magnetic stirring reaction for 3 hours, after the reaction is finished, performing reduced pressure concentration on the reaction solution, and performing silica gel column chromatography separation on the obtained concentrate, wherein the volume ratio of petroleum ether to ethyl acetate is 80: 1 as eluent, collecting the eluent containing the target product, evaporating the solvent and drying to obtain 0.549g of white solid product 2-benzylthio-4-chloroquinoline-3-methyl formate 2i with the yield of 80%.

The above reaction formula is as follows:

preparation of product 2-benzylthio-4-chloroquinoline-3-carboxylic acid methyl ester 2i¹H NMR and¹³the C NMR data are as follows:

¹H NMR(300MHz,CDCl₃):δ＝4.00(s,3H),4.62(s,2H),7.35–7.17(m,3H),7.51–7.35(m,2H),7.56(ddd,J＝8.3,6.9,1.2Hz,1H),7.75(ddd,J＝8.4,7.0,1.4Hz,1H),8.00(dd,J＝8.5,0.6Hz,1H),8.16(dd,J＝8.7,1.1Hz,1H)；¹³C NMR(75MHz,CDCl₃):δ＝34.8,53.0,123.1,124.5,125.5,126.7,127.1,128.1,128.3,129.2,131.4,137.1,139.4,147.8,155.6,165.2。

EXAMPLE 102 Synthesis of methyl ethylthio-4-chloro-6-iodoquinoline-3-carboxylate

Adding 10mL of chlorobenzene and 0.594g of BTC (2.0mmol) into a 38mL thick-wall pressure-resistant bottle provided with a magnetic stirrer at room temperature, dissolving the chlorobenzene and the BTC at room temperature, adding 0.842g N and S-ketene acetal 1j (2.0mmol), sealing a reaction system, heating to 120 ℃, continuing to perform magnetic stirring reaction for 5 hours, after the reaction is finished, performing reduced pressure concentration on the reaction solution, and performing silica gel column chromatography separation on the obtained concentrate, wherein the volume ratio of petroleum ether to ethyl acetate is 60: 1 as eluent, collecting the eluent containing the target product, evaporating the solvent and drying to obtain 0.611g of a pale yellow solid product 2-ethylthio-4-chloro-6-iodoquinoline-3-methyl formate 2j with a yield of 75%.

The above reaction formula is as follows:

preparation of product 4-chloro-2-ethylsulfanyl-6-iodoquinoline-3-carboxylic acid methyl ester 2j¹H NMR and¹³the C NMR data are as follows:

¹H NMR(300MHz,CDCl₃):δ＝1.41(t,J＝7.3Hz,3H),3.36(q,J＝7.4Hz,2H),4.03(s,3H),8.26～8.29(m,1H),7.69(d,J＝8.8Hz,1H),7.96(dd,J＝8.8,1.9Hz,1H),8.50(d,J＝1.9Hz,1H)；¹³C NMR(75MHz,CDCl₃):δ＝14.0,25.0,53.1,91.8,124.4,126.4,129.6,133.1,137.6,139.9,146.8,157.0,164.9。

EXAMPLE 112 Synthesis of Ethylthio-4-chloroquinoline-3-carboxylic acid ethyl ester

Adding 10mL of chlorobenzene and 0.594g of BTC (2.0mmol) into a 38mL thick-wall pressure-resistant bottle provided with a magnetic stirrer at room temperature, dissolving the chlorobenzene and the BTC at room temperature, adding 0.646g N, S-ketene acetal 1k (2.0mmol), heating a reaction system to 120 ℃, continuing to perform magnetic stirring reaction for 4 hours, after the reaction is finished, performing reduced pressure concentration on the reaction solution, and performing silica gel column chromatography separation on the obtained concentrate, wherein the volume ratio of petroleum ether to ethyl acetate is 70: 1 as eluent, collecting the eluent containing the target product, evaporating the solvent and drying to obtain 0.531g of a light yellow solid product 2-ethylthio-4-chloroquinoline-3-ethyl formate 2k with a yield of 90%.

The above reaction formula is as follows:

preparation of product 2-ethylsulfanyl-4-chloroquinoline-3-carboxylic acid ethyl ester 2k¹H NMR and¹³the C NMR data are as follows:

¹H NMR(300MHz,CDCl₃):δ＝1.45(dt,J＝10.5,7.2Hz,6H),3.38(q,J＝7.4Hz,2H),4.52(q,J＝7.1Hz,2H),7.54(ddd,J＝8.3,7.0,1.2Hz,1H),7.73(ddd,J＝8.5,7.0,1.5Hz,1H),7.96(ddd,J＝8.4,1.2,0.6Hz,1H),8.15(ddd,J＝8.4,1.5,0.6Hz,1H)；¹³C NMR(75MHz,CDCl₃):δ＝13.9,14.1,62.3,122.9,124.4,126.3,126.4,128.1,131.1,138.8,147.9,155.9,164.9。

example 122 Synthesis of methyl methylsulfanyl-4-chloro-quinoline-3-carboxylate

Adding 11mL of chlorobenzene and 0.594g of BTC (2.0mmol) into a 38mL thick-wall pressure-resistant bottle provided with a magnetic stirrer at room temperature, dissolving the chlorobenzene and the BTC at room temperature, adding 0.562g N and 1l (2.0mmol) of S-ketene into the solution, heating a reaction system to 120 ℃, continuing to perform magnetic stirring reaction for 3 hours, after the reaction is finished, performing reduced pressure concentration on the reaction solution, and performing silica gel column chromatography separation on the obtained concentrate, wherein the volume ratio of petroleum ether to ethyl acetate is 60: 1 as eluent, and collecting the eluent containing the target product, evaporating the solvent and drying to obtain 0.427g of a pale yellow solid product, 2l of methyl 2-methylthio-4-chloro-quinoline-3-carboxylate, with a yield of 80%.

The above reaction formula is as follows:

preparation of product 2l methyl 2-methylsulfanyl-4-chloroquinoline-3-carboxylate¹H NMR and¹³the C NMR data are as follows:

¹H NMR(300MHz,CDCl₃):δ＝2.71(s,3H),4.04(s,3H),7.60–7.49(m,1H),7.84–7.68(m,1H),7.97(d,J＝8.4Hz,1H),8.15(d,J＝8.5Hz,1H)；¹³C NMR(75MHz,CDCl₃):δ＝13.5,53.0,122.9,124.6,125.8,126.6,128.1,131.3,139.1,147.9,156.3,165.4。