A method for synthesizing 6-(3,3-diethoxypropyl)quinoline, an intermediate of carmatinib.

Abstract

This invention relates to the field of pharmaceutical intermediate synthesis technology, specifically disclosing a method for synthesizing 6-(3,3-diethoxypropyl)quinoline, an intermediate of carmatinib. This invention provides a novel synthetic route for 6-(3,3-diethoxypropyl)quinoline, an intermediate of carmatinib. The method uses 6-bromoquinoline and acrolein diethanol condensate as starting materials, and palladium dichloride bis(triphenylphosphine) as a catalyst. Compound I is first prepared via a Heck coupling reaction, and then compound I is hydrogenated to obtain 6-(3,3-diethoxypropyl)quinoline. The method for preparing 6-(3,3-diethoxypropyl)quinoline, an intermediate of carmatinib, provided by this invention has the advantages of reasonable process design, high product yield and purity, and low production cost, which is conducive to the large-scale production of carmatinib and is of great significance for promoting the widespread application of carmatinib in the field of tumor treatment.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediate synthesis technology, and in particular to a method for synthesizing 6-(3,3-diethoxypropyl)quinoline, an intermediate of carmatinib. Background Technology

[0002] Carmatinib's chemical name is 2-fluoro-N-methyl-4-[7-[(quinolin-6-yl)methyl]imidazo[1,2-B]-[1,2,4]triazin-2-yl]benzamide, with the molecular formula C 23 H 117 FN6O, CAS Registry No.: 1029712-80-8, has the following structural formula. Carmatinib is an orally administered, highly selective small-molecule MET inhibitor primarily used to treat patients with MET gene mutation-positive locally advanced or metastatic non-small cell lung cancer (NSCLC). Carmatinib has also been widely used in clinical trials investigating melanoma, glioma, solid tumors, colorectal cancer, and liver injury.

[0003]

[0004] 6-(3,3-diethoxypropyl)quinoline is a key intermediate in the preparation of carmatinib. Currently, the methods for preparing this intermediate are mainly divided into two-step and one-step methods. In the two-step method (process route as follows), the first step requires palladium acetate as a catalyst, which is expensive and has high material costs.

[0005]

[0006] The one-step process (as shown below) requires palladium acetate and 9-BBN as catalysts, which also suffers from high cost and high material costs. Therefore, it is necessary to develop a novel process for synthesizing 6-(3,3-diethoxypropyl)quinoline to reduce the synthesis cost of carmatinib and promote its widespread application in cancer treatment.

[0007] Summary of the Invention

[0008] To address the problems of high cost and limited large-scale production and application of carmatinib intermediate 6-(3,3-diethoxypropyl)quinoline in existing technologies, this invention provides a method for synthesizing carmatinib intermediate 6-(3,3-diethoxypropyl)quinoline.

[0009] To solve the above-mentioned technical problems, the technical solution provided by the present invention is as follows:

[0010] A method for synthesizing 6-(3,3-diethoxypropyl)quinoline, an intermediate in carmatinib, comprising the following steps:

[0011] S1, under alkaline conditions, 6-bromoquinoline and acrolein diethanol condensate were subjected to a Heck coupling reaction using palladium dichloride as a catalyst to give compound I;

[0012]

[0013] S2, compound I is subjected to hydrogenation reduction to give 6-(3,3-diethoxypropyl)quinoline.

[0014] Compared to existing technologies, this invention provides a novel synthetic route for the carmatinib intermediate 6-(3,3-diethoxypropyl)quinoline. This method uses 6-bromoquinoline and acrolein diethanol condensate as starting materials, and palladium dichloride bis(triphenylphosphine) as a catalyst. Compound I is first prepared via a Heck coupling reaction, and then reduced by hydrogenation to obtain the carmatinib intermediate 6-(3,3-diethoxypropyl)quinoline. The preparation method of carmatinib intermediate 6-(3,3-diethoxypropyl)quinoline provided by this invention has the advantages of reasonable process design, high product yield and purity, and low production cost, which is conducive to the large-scale production of carmatinib and is of great significance for promoting the widespread application of carmatinib in the field of cancer treatment.

[0015] Compared to the original method which uses expensive palladium acetate as the catalyst in step one, this invention uses palladium dichloride of bis(triphenylphosphine) as the catalyst. While ensuring the yield and purity of the intermediate 6-(3,3-diethoxypropyl)quinoline, it effectively reduces the cost of the catalyst (the cost of the catalyst is reduced by about 180 yuan / 10g), providing a completely new process route for the production of carmatinib, and has high practical and promotional value.

[0016] As a specific embodiment of the present invention, the method for synthesizing the carmatinib intermediate 6-(3,3-diethoxypropyl)quinoline specifically includes the following steps:

[0017] Step 1: Add 6-bromoquinoline, acrylaldehyde diethanol and base to the first solvent, and under an inert atmosphere, add palladium dichloride of bis(triphenylphosphine) to carry out the Heck coupling reaction to obtain compound I;

[0018] Step 2: Add compound I and the catalyst to the second solvent, introduce hydrogen gas, and carry out a hydrogenation reduction reaction to obtain 6-(3,3-diethoxypropyl)quinoline.

[0019] The reaction equations for the above preparation process are as follows:

[0020]

[0021] Preferably, in step one, the first solvent is N,N-dimethylformamide.

[0022] Preferably, in step one, the alkali is potassium carbonate.

[0023] Preferably, in step one, the molar ratio of 6-bromoquinoline, acrolein diethanol, bis(triphenylphosphine) palladium dichloride and the base is 1:(1.5-2):(0.01-0.1):(1.5-2).

[0024] Preferably, in step one, the mass-to-volume ratio of 6-bromoquinoline to the first solvent is 1 g:(2-5) mL.

[0025] Preferably, in step one, the temperature of the Heck coupling reaction is 70℃~90℃, and the reaction time is 3h~6h.

[0026] The preferred reaction conditions in step one can promote the full reaction of 6-bromoquinoline with acrolein diethyl acetal, and at the same time, they are also beneficial to increasing the reaction rate of the Heck coupling reaction.

[0027] It should be noted that after the reaction in step one is completed, a post-processing procedure is also included: water and acetic acid are added to the reaction solution, mixed evenly, and the solid and liquid phases are separated. The resulting aqueous phase is allowed to stand and separated, while the organic phase is retained. The aqueous phase is extracted with ethyl acetate, and the organic phases are combined. The organic phase is washed with saturated brine and concentrated under reduced pressure to obtain crude compound I. The crude product is then separated by column chromatography to obtain compound I.

[0028] Specifically, the column chromatography packing material is 200-300 mesh silica gel, and the eluent is n-hexane and ethyl acetate in a volume ratio of 10:1.

[0029] Preferably, in step two, the catalyst is a palladium-on-carbon catalyst.

[0030] Preferably, in step two, the second solvent is tetrahydrofuran.

[0031] Preferably, in step two, the mass ratio of compound I to the catalyst is 1:(0.05-0.2).

[0032] Preferably, in step two, the temperature of the hydrogenation reduction reaction is 10℃~40℃, the reaction pressure is 0.3atm~1atm, and the reaction time is 18h~24h.

[0033] Preferably, in step two, the mass-to-volume ratio of compound I to the second solvent is 1 g:(3-5) mL.

[0034] The preferred reaction conditions in step two can promote the full progress of the hydrogenation reduction reaction of compound I (1) and improve the yield and purity of 6-(3,3-diethoxypropyl)quinoline.

[0035] It should be noted that after the reaction in step two is completed, a post-processing procedure is also included: the reaction solution is filtered, the filtrate is concentrated, and column chromatography is performed to obtain 6-(3,3-diethoxypropyl)quinoline.

[0036] Specifically, the column chromatography packing material is 200-300 mesh silica gel, and the eluent is n-hexane and ethyl acetate in a volume ratio of 5:1.

[0037] The method for synthesizing 6-(3,3-diethoxypropyl)quinoline, an intermediate of carmatinib, provided by this invention avoids the use of expensive catalysts, effectively reducing production costs. It also ensures the purity and yield of 6-(3,3-diethoxypropyl)quinoline, providing a novel process route for the preparation of carmatinib. The development of this method strongly supports the widespread application of carmatinib and brings new hope to the field of tumor treatment, possessing high value for promotion and application. Attached Figure Description

[0038] Figure 1 The 1H NMR spectrum of compound I prepared in Example 1 of this invention;

[0039] Figure 2 The 1H NMR spectrum of 6-(3,3-diethoxypropyl)quinoline, the carmatinib intermediate prepared in Example 1 of this invention. Detailed Implementation

[0040] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0041] Example 1

[0042] This embodiment provides a method for preparing the carmatinib intermediate 6-(3,3-diethoxypropyl)quinoline, and the process route is as follows:

[0043]

[0044] Step 1: Add 10.50g (0.05mol) of 6-bromoquinoline, 10.51g (0.08mol) of acrolein diethanol, 12.56g (0.09mol) of potassium carbonate, and 21mL of [unspecified ingredient] to a 100mL three-necked flask in sequence. N,N-Dimethylformamide was used. The air in the three-necked flask was replaced with nitrogen. Under nitrogen purging, 1.41 g (0.002 mol) of bis(triphenylphosphine)palladium dichloride was added. The mixture was heated to 80 °C and reacted for 4 h. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. 20 mL each of water and ethyl acetate were added to the reaction system, and the mixture was stirred for 20 min. The mixture was filtered through diatomaceous earth. The filtrate was allowed to stand and the phases separated. The organic phase was retained, and the aqueous phase was extracted with ethyl acetate (20 mL * 2). The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography at 200-300 μM (n-hexane:ethyl acetate = 10:1) to obtain 12.48 g of a yellow oily compound I, with a yield of 96.2%.

[0045] 1 H NMR (400MHz, DMSO-d6): δ8.88(dd,J=4.3,1.7Hz,1H),8.34(dd,J=8.4,1.7Hz,1H),8.04–7.96(m,3H),7.54(dd,J=8.3,4.2Hz,1H),6.89( d, J=16.1Hz, 1H), 6.47 (dd, J=16.1, 5.3Hz, 1H), 5.14 (dd, J=5..4, 1.1Hz, 1H), 3.60 (ddq, J=49.0, 9.6, 7.1Hz, 4H), 1.19 (t, J=7.0Hz, 6H).

[0046] Liquid chromatography-mass spectrometry [M+H] + m / z: Calculated value 258.14, measured value 258.25.

[0047] Step 2: Add 5g (0.02mol) of the prepared 6-(3,3-diethoxypropyl-1-en-1-yl)quinoline, 0.5g of palladium on carbon, and 20mL of tetrahydrofuran sequentially to the reaction vessel. Replace the air in the reaction vessel with hydrogen gas and react for 18h under 1atm hydrogen atmosphere. After the reaction is complete as monitored by TLC, filter with diatomaceous earth, concentrate the filtrate under reduced pressure to obtain the crude product. Purify the crude product by silica gel column chromatography at 200-300 μm (n-hexane:ethyl acetate = 5:1) to obtain a yellow oily substance, namely 4.82g of 6-(3,3-diethoxypropyl)quinoline, with a yield of 95.8%.

[0048] 1H NMR (400MHz, DMSO-d6): δ8.86 (dt, J=4.2, 1.4Hz, 1H), 8.30 (dd, J=8.3, 1.7Hz, 1H),7.96(d,J=8.6Hz,1H),7.79(d,J=2.0Hz,1H),7.69–7.64(m,1H),7.54–7.4 8(m,1H),4.51(t,J=5.6Hz,1H),3.66–3.56(m,2H),3.46(dq,J=9.3,7.0Hz,2H ), 2.82 (dd, J = 9.4, 6.5 Hz, 2H), 1.98–1.90 (m, 2H), 1.14 (td, J = 7.0, 1.0 Hz, 6H).

[0049] Liquid chromatography-mass spectrometry [M+H] + m / z: Calculated value 260.16, measured value 260.28.

[0050] Example 2

[0051] This embodiment provides a method for preparing the carmatinib intermediate 6-(3,3-diethoxypropyl)quinoline, and the process route is as follows:

[0052]

[0053] Step 1: Add 10.50g (0.05mol) of 6-bromoquinoline, 9.95g (0.076mol) of acrolein diethanol, 10.65g (0.077mol) of potassium carbonate, and 32mL of [unspecified ingredient] to a 100mL three-necked flask in sequence. N,N-Dimethylformamide was used. The air in the three-necked flask was replaced with nitrogen. Under nitrogen purging, 0.46 g (0.006 mol) of bis(triphenylphosphine)palladium dichloride was added. The mixture was heated to 90 °C and reacted for 6 h. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. 20 mL each of water and ethyl acetate were added to the reaction system, and the mixture was stirred for 20 min. The mixture was filtered through diatomaceous earth. The filtrate was allowed to stand and the phases separated. The organic phase was retained, and the aqueous phase was extracted with ethyl acetate (20 mL * 2). The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography at 200-300 μM (n-hexane:ethyl acetate = 10:1) to obtain 12.31 g of a yellow oily compound I, with a yield of 94.8%.

[0054] 1H NMR (400MHz, DMSO-d6): δ8.88(dd,J=4.3,1.7Hz,1H),8.34(dd,J=8.4,1.7Hz,1H),8.04–7.96(m,3H),7.54(dd,J=8.3,4.2Hz,1H),6.89( d, J=16.1Hz, 1H), 6.47 (dd, J=16.1, 5.3Hz, 1H), 5.14 (dd, J=5..4, 1.1Hz, 1H), 3.60 (ddq, J=49.0, 9.6, 7.1Hz, 4H), 1.19 (t, J=7.0Hz, 6H).

[0055] Liquid chromatography-mass spectrometry [M+H] + m / z: Calculated value 258.14, measured value 258.25.

[0056] Step 2: Add 5g (0.02mol) of the prepared 6-(3,3-diethoxypropyl-1-en-1-yl)quinoline, 0.25g of palladium on carbon, and 15mL of tetrahydrofuran sequentially to the reaction vessel. Replace the air in the reaction vessel with hydrogen gas and react for 24h at 0.6 atm hydrogen. After the reaction is complete, monitor the reaction by TLC. Filter with diatomaceous earth, concentrate the filtrate under reduced pressure to obtain the crude product. Purify the crude product by silica gel column chromatography at 200-300 μm (n-hexane:ethyl acetate = 5:1) to obtain a yellow oily substance, namely 4.87g of 6-(3,3-diethoxypropyl)quinoline, with a yield of 96.8%.

[0057] 1 H NMR (400MHz, DMSO-d6): δ8.86 (dt, J=4.2, 1.4Hz, 1H), 8.30 (dd, J=8.3, 1.7Hz, 1H),7.96(d,J=8.6Hz,1H),7.79(d,J=2.0Hz,1H),7.69–7.64(m,1H),7.54–7.4 8(m,1H),4.51(t,J=5.6Hz,1H),3.66–3.56(m,2H),3.46(dq,J=9.3,7.0Hz,2H ), 2.82 (dd, J = 9.4, 6.5 Hz, 2H), 1.98–1.90 (m, 2H), 1.14 (td, J = 7.0, 1.0 Hz, 6H).

[0058] Liquid chromatography-mass spectrometry [M+H] + m / z: Calculated value 260.16, measured value 260.28.

[0059] Example 3

[0060] This embodiment provides a method for preparing the carmatinib intermediate 6-(3,3-diethoxypropyl)quinoline, and the process route is as follows:

[0061]

[0062] Step 1: Add 10.50g (0.05mol) of 6-bromoquinoline, 13.15g (0.10mol) of acrolein diethanol, 13.96g (0.10mol) of potassium carbonate, and 45mL of [unspecified ingredient] to a 100mL three-necked flask in sequence. N,N-Dimethylformamide was used. The air in the three-necked flask was replaced with nitrogen. Under nitrogen purging, 3.55 g (0.005 mol) of bis(triphenylphosphine) palladium dichloride was added. The mixture was heated to 70 °C and reacted for 3 h. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature. 20 mL each of water and ethyl acetate were added to the reaction system, and the mixture was stirred for 20 min. The mixture was filtered through diatomaceous earth. The filtrate was allowed to stand and the phases separated. The organic phase was retained, and the aqueous phase was extracted with ethyl acetate (20 mL * 2). The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography at 200-300 μM (n-hexane:ethyl acetate = 10:1) to obtain 12.37 g of a yellow oily compound I, with a yield of 95.3%.

[0063] 1 H NMR (400MHz, DMSO-d6): δ8.88(dd,J=4.3,1.7Hz,1H),8.34(dd,J=8.4,1.7Hz,1H),8.04–7.96(m,3H),7.54(dd,J=8.3,4.2Hz,1H),6.89 (d, J=16.1Hz, 1H), 6.47 (dd, J=16.1, 5.3Hz, 1H), 5.14 (dd, J=5.4, 1.1Hz, 1H), 3.60 (ddq, J=49.0, 9.6, 7.1Hz, 4H), 1.19 (t, J=7.0Hz, 6H).

[0064] Liquid chromatography-mass spectrometry [M+H] + m / z: Calculated value 258.14, measured value 258.25.

[0065] Step 2: Add 5g (0.02mol) of the prepared 6-(3,3-diethoxypropyl-1-en-1-yl)quinoline, 1g of palladium on carbon, and 25mL of tetrahydrofuran sequentially to the reaction vessel. Replace the air in the reaction vessel with hydrogen gas and react for 18h under 0.3 atm hydrogen gas. After the reaction is complete, monitor the reaction by TLC. Filter with diatomaceous earth, concentrate the filtrate under reduced pressure to obtain the crude product. Purify the crude product by silica gel column chromatography at 200-300 μm (n-hexane:ethyl acetate = 5:1) to obtain a yellow oily substance, namely 4.74g of 6-(3,3-diethoxypropyl)quinoline, with a yield of 94.2%.

[0066] 1H NMR (400MHz, DMSO-d6): δ8.86 (dt, J=4.2, 1.4Hz, 1H), 8.30 (dd, J=8.3, 1.7Hz, 1H),7.96(d,J=8.6Hz,1H),7.79(d,J=2.0Hz,1H),7.69–7.64(m,1H),7.54–7.4 8(m,1H),4.51(t,J=5.6Hz,1H),3.66–3.56(m,2H),3.46(dq,J=9.3,7.0Hz,2H ), 2.82 (dd, J = 9.4, 6.5 Hz, 2H), 1.98–1.90 (m, 2H), 1.14 (td, J = 7.0, 1.0 Hz, 6H).

[0067] Liquid chromatography-mass spectrometry [M+H] + m / z: Calculated value 260.16, measured value 260.28.

[0068] Comparative Example 1

[0069] This comparative example provides a method for preparing the carmatinib intermediate 6-(3,3-diethoxypropyl)quinoline, specifically including the following steps:

[0070] 10.50 g (0.05 mol) of 6-bromoquinoline, 10.51 g (0.08 mol) of acrolein diethanolamide, 12.56 g (0.09 mol) of potassium carbonate, and 21 mL of N,N-dimethylformamide were added sequentially to a 100 mL three-necked flask. The air in the flask was replaced with nitrogen, and 2.31 g (0.002 mol) of tetrakis(triphenylphosphine)palladium was added under nitrogen purging. The mixture was heated to 80 °C and reacted for 16 h. TLC monitoring showed no obvious product spot. This demonstrates that tetrakis(triphenylphosphine)palladium cannot catalyze the Heck coupling reaction between 6-bromoquinoline and acrolein diethanolamide.

[0071] Comparative Example 2

[0072] This comparative example provides a method for preparing the carmatinib intermediate 6-(3,3-diethoxypropyl)quinoline, specifically including the following steps:

[0073] 10.50 g (0.05 mol) of 6-bromoquinoline, 10.51 g (0.08 mol) of acrolein diacetate, 12.56 g (0.09 mol) of potassium carbonate, and 21 mL of N,N-dimethylformamide were added sequentially to a 100 mL three-necked flask. The air in the flask was replaced with nitrogen, and 0.74 g (0.002 mol) of triphenylphosphine palladium was added under nitrogen purging. The mixture was heated to 80 °C and reacted for 16 h. TLC monitoring showed no obvious product spot. This demonstrates that triphenylphosphine palladium cannot catalyze the Heck coupling reaction between 6-bromoquinoline and acrolein diacetate.

[0074] Comparative Example 3

[0075] This comparative example provides a method for preparing the carmatinib intermediate 6-(3,3-diethoxypropyl)quinoline, specifically including the following steps:

[0076] 10.50 g (0.05 mol) of 6-bromoquinoline, 10.51 g (0.08 mol) of acrolein diethanolamide, 12.56 g (0.09 mol) of potassium carbonate, and 21 mL of N,N-dimethylformamide were added sequentially to a 100 mL three-necked flask. The air in the flask was replaced with nitrogen, and 2.3 g of palladium on carbon was added under nitrogen purging. The mixture was heated to 80 °C and reacted for 16 h. TLC monitoring showed no obvious product spot. This demonstrates that the palladium on carbon catalyst cannot catalyze the Heck coupling reaction between 6-bromoquinoline and acrolein diethanolamide.

[0077] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions or improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for synthesizing 6-(3,3-diethoxypropyl)quinoline, an intermediate in carmatinib, characterized in that, Includes the following steps: Step 1: Under alkaline conditions, 6-bromoquinoline and acrolein diethanol condensate were subjected to a Heck coupling reaction using palladium dichloride as a catalyst to obtain compound I. Step 2: Compound I is subjected to a hydrogenation reduction reaction to obtain 6-(3,3-diethoxypropyl)quinoline.

2. The method for synthesizing the carmatinib intermediate 6-(3,3-diethoxypropyl)quinoline as described in claim 1, characterized in that, Specifically, the steps include the following: Step 1: Add 6-bromoquinoline, acrylaldehyde diethanol and base to the first solvent, and under an inert atmosphere, add palladium dichloride of bis(triphenylphosphine) to carry out the Heck coupling reaction to obtain compound I; Step 2: Add compound I and the catalyst to the second solvent, introduce hydrogen gas, and carry out a hydrogenation reduction reaction to obtain 6-(3,3-diethoxypropyl)quinoline.

3. The method for synthesizing the carmatinib intermediate 6-(3,3-diethoxypropyl)quinoline as described in claim 2, characterized in that, In step one, the first solvent is N,N-dimethylformamide; and / or In step one, the alkali is potassium carbonate.

4. The method for synthesizing the carmatinib intermediate 6-(3,3-diethoxypropyl)quinoline as described in claim 2, characterized in that, In step two, the catalyst is a palladium-on-carbon catalyst; and / or In step two, the second solvent is tetrahydrofuran.

5. The method for synthesizing the carmatinib intermediate 6-(3,3-diethoxypropyl)quinoline as described in claim 2, characterized in that, In step one, the molar ratio of 6-bromoquinoline, acrolein diethanol, bis(triphenylphosphine) palladium dichloride and the base is 1:(1.5-2):(0.01-0.1):(1.5-2).

6. The method for synthesizing the carmatinib intermediate 6-(3,3-diethoxypropyl)quinoline as described in claim 2, characterized in that, In step one, the mass-to-volume ratio of 6-bromoquinoline to the first solvent is 1 g:(2-5) mL.

7. The method for synthesizing the carmatinib intermediate 6-(3,3-diethoxypropyl)quinoline as described in claim 2, characterized in that, In step one, the temperature of the Heck coupling reaction is 70℃~90℃, and the reaction time is 3h~6h.

8. The method for synthesizing the carmatinib intermediate 6-(3,3-diethoxypropyl)quinoline as described in claim 2, characterized in that, In step two, the mass ratio of compound I to the catalyst is 1:(0.05-0.2).

9. The method for synthesizing the carmatinib intermediate 6-(3,3-diethoxypropyl)quinoline as described in claim 2, characterized in that, In step two, the temperature of the hydrogenation reduction reaction is 10℃~40℃, the reaction pressure is 0.3atm~1atm, and the reaction time is 18h~24h.

10. The method for synthesizing the carmatinib intermediate 6-(3,3-diethoxypropyl)quinoline as described in claim 2, characterized in that, In step two, the mass-to-volume ratio of compound I to the second solvent is 1 g:(3-5) mL.

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