Synthetic method of carbamatinib intermediate 6-(3, 3-diethoxy propyl) quinoline

Abstract

The invention relates to the technical field of synthesis of drug intermediates, and particularly discloses a synthesis method of a carbamatinib intermediate 6-(3, 3-diethoxy propyl) quinoline. The invention provides a novel synthesis method of a carbamatinib intermediate 6-(3, 3-diethoxy propyl) quinoline by designing a novel synthesis route, and the method comprises the following steps: by taking 6-bromoquinoline and acrolein diethyl acetal as initial raw materials and bis (triphenylphosphine) palladium dichloride as a catalyst, firstly preparing a compound I through a Heck coupling reaction, and then preparing a compound II through the Heck coupling reaction to obtain the carbamatinib intermediate 6-(3, 3-diethoxy propyl) quinoline through the synthesis of the carbamatinib intermediate 6-(3, 3-diethoxy propyl) quinoline. And then carrying out hydrogenation reduction on the compound I to obtain 6-(3, 3-diethoxy propyl) quinoline. The preparation method of the carbamatinib intermediate 6-(3, 3-diethoxypropyl) quinoline provided by the invention has the advantages of reasonable process design, high product yield and purity and low production cost, is favorable for realizing large-scale production of the carbamatinib, and has very important significance for promoting wide application of the carbamatinib in the field of tumor treatment.

Description

Technical Field

[0001] The invention relates to the technical field of drug intermediate synthesis, and in particular to a method for synthesizing a capmatinib intermediate 6-(3,3-diethoxypropyl)quinoline. Background Art

[0002] The chemical name of Capmatinib is 2-fluoro-N-methyl-4-[7-[(quinolin-6-yl)methyl]imidazo[1,2-B]-[1,2,4]triazine-2-yl]benzamide, with a molecular formula of C 23 H 117 FN 6 O, CAS registration number: 1029712-80-8, the structural formula is as follows. Capmatinib is an oral, highly selective small molecule MET inhibitor, mainly used to treat patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with positive MET gene mutations. Capmatinib is also widely used in clinical trials for melanoma, gliosarcoma, solid tumors, colorectal cancer and liver damage.

[0003]

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

[0005]

[0006] The one-step process route (as shown below) requires palladium acetate and 9-BBN as catalysts, which also have the problems of high price and high material cost. Therefore, it is necessary to develop a new process for synthesizing 6-(3,3-diethoxypropyl)quinoline to reduce the synthesis cost of capmatinib and promote the wide application of capmatinib in the field of tumor treatment.

[0007] Summary of the invention

[0008] In view of the problems that the process for preparing a capmatinib intermediate 6-(3,3-diethoxypropyl)quinoline in the prior art is high in cost and limits the large-scale production and application of capmatinib, the present invention provides a method for synthesizing a capmatinib intermediate 6-(3,3-diethoxypropyl)quinoline.

[0009] In order to solve the above technical problems, the technical solution provided by the present invention is:

[0010] A method for synthesizing a capmatinib intermediate 6-(3,3-diethoxypropyl)quinoline comprises the following steps:

[0011] S1, under alkaline conditions, using bistriphenylphosphine palladium dichloride as a catalyst, 6-bromoquinoline and acrolein diethyl acetal undergo Heck coupling reaction to obtain compound Ⅰ;

[0012]

[0013] S2, subjecting compound I to hydrogenation reduction reaction to obtain 6-(3,3-diethoxypropyl)quinoline.

[0014] Compared with the prior art, the present invention provides a new synthesis method of a capmatinib intermediate 6-(3,3-diethoxypropyl)quinoline by designing a new synthesis route. The method uses 6-bromoquinoline and acrolein diethyl acetal as starting materials, uses bistriphenylphosphine palladium dichloride as a catalyst, and first prepares compound I through a Heck coupling reaction, and then compound I is hydrogenated and reduced to obtain the capmatinib intermediate 6-(3,3-diethoxypropyl)quinoline. The preparation method of the capmatinib intermediate 6-(3,3-diethoxypropyl)quinoline provided by the present 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 capmatinib, and is of great significance for promoting the wide application of capmatinib in the field of tumor treatment.

[0015] Compared with the original method using expensive palladium acetate as the catalyst for step one, the present invention uses bistriphenylphosphine palladium dichloride as the catalyst, and effectively reduces the cost of the catalyst (the catalyst cost is reduced by about 180 yuan / 10g) while ensuring the yield and purity of the intermediate 6-(3,3-diethoxypropyl)quinoline, thereby providing a new process route for the production of capmatinib and having high practical promotion value.

[0016] As a specific embodiment of the present invention, the synthesis method of the capmatinib intermediate 6-(3,3-diethoxypropyl)quinoline specifically comprises the following steps:

[0017] Step 1, 6-bromoquinoline, propylene acetal diethanol and a base are added to a first solvent, and bistriphenylphosphine palladium dichloride is added under an inert atmosphere to carry out a Heck coupling reaction to obtain compound I;

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

[0019] The reaction equation of the above preparation process is as follows:

[0020]

[0021] Preferably, in step 1, the first solvent is N,N-dimethylformamide.

[0022] Preferably, in step 1, the base is potassium carbonate.

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

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

[0025] Preferably, in step 1, the temperature of the Heck coupling reaction is 70° C. to 90° C., and the reaction time is 3 h to 6 h.

[0026] The preferred reaction conditions in step 1 can promote the full reaction of 6-bromoquinoline and acrolein diethyl acetal, and at the same time, are also beneficial to improving the reaction rate of the Heck coupling reaction.

[0027] It should be noted that after the reaction in step 1 is completed, a post-treatment process is also included: water and ethyl acetate are added to the reaction solution, mixed evenly, solid-liquid separation is performed, the obtained aqueous phase is allowed to stand for separation, the organic phase is retained, the aqueous phase is extracted with ethyl acetate, the organic phases are combined, the organic phases are washed with saturated brine, and concentrated under reduced pressure to obtain a crude product of compound I; the crude product is separated by column chromatography to obtain compound I.

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

[0029] Preferably, in step 2, the catalyst is a palladium-carbon catalyst.

[0030] Preferably, in step 2, the second solvent is tetrahydrofuran.

[0031] Preferably, in step 2, the mass ratio of compound I to catalyst is 1:(0.05-0.2).

[0032] Preferably, in step 2, the temperature of the hydrogenation reduction reaction is 10° C. to 40° C., the reaction pressure is 0.3 atm to 1 atm, and the reaction time is 18 h to 24 h.

[0033] Preferably, in step 2, the mass volume ratio of the compound I to the second solvent is 1 g: (3-5) mL.

[0034] The preferred reaction conditions in step 2 can promote the full 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 2 is completed, a post-treatment process is also included: filtering the reaction solution, concentrating the filtrate, and performing column chromatography to obtain 6-(3,3-diethoxypropyl)quinoline.

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

[0037] The method for synthesizing the capmatinib intermediate 6-(3,3-diethoxypropyl)quinoline provided by the present invention avoids the use of expensive catalysts, effectively reduces production costs, and also ensures the purity and yield of the capmatinib intermediate 6-(3,3-diethoxypropyl)quinoline, thereby providing a new process route for preparing capmatinib. The development of this method provides strong support for the widespread application of capmatinib, and also brings new hope to the field of tumor treatment, and has high promotion and application value. BRIEF DESCRIPTION OF THE DRAWINGS

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

[0039] Figure 2 This is the H NMR spectrum of the capmatinib intermediate 6-(3,3-diethoxypropyl)quinoline prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0040] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0041] Example 1

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

[0043]

[0044] Step 1: Add 10.50 g (0.05 mol) of 6-bromoquinoline, 10.51 g (0.08 mol) of acrolein diethyl acetal, 12.56 g (0.09 mol) of potassium carbonate and 21 mL of N,N-dimethylformamide, replace the air in the three-necked flask with nitrogen, add 1.41g (0.002mol) of bistriphenylphosphine palladium dichloride under nitrogen purge, heat to 80℃ and react for 4h. After the reaction is completed under TLC monitoring, cool to room temperature, add 20mL of water and ethyl acetate respectively to the reaction system, stir for 20min, filter through diatomaceous earth, take the filtrate and let it stand for phase separation, retain the organic phase, extract the aqueous phase with ethyl acetate (20mL*2), combine the organic phases, wash with saturated brine, and concentrate under reduced pressure to obtain a crude product; the crude product is purified by 200-300 silica gel column chromatography (n-hexane:ethyl acetate=10:1) to obtain 12.48g of yellow oily compound I with a yield of 96.2%.

[0045] 1 H NMR (400 MHz, DMSO-d 6 ): 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=16.1H z, 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 mass [M+H] + m / z: calculated value 258.14, found value 258.25.

[0047] Step 2: Add 5 g (0.02 mol) of the prepared 6-(3,3-diethoxyprop-1-en-1-yl)quinoline, 0.5 g of palladium on carbon and 20 mL of tetrahydrofuran to the reaction vessel in sequence, replace the air in the reaction vessel with hydrogen, react for 18 h under 1 atm of hydrogen, and after the reaction is completed by TLC monitoring, filter with diatomaceous earth, and concentrate the filtrate under reduced pressure to obtain a crude product; the crude product is purified by 200-300 silica gel column chromatography (n-hexane: ethyl acetate = 5:1) to obtain a yellow oil, i.e. 4.82 g of 6-(3,3-diethoxypropyl)quinoline, with a yield of 95.8%.

[0048] 1 H NMR (400 MHz, DMSO-d 6): 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),7.54–7.48(m,1H),4 .51(t,J=5.6Hz,1H),3.66–3.56(m,2H),3.46(dq,J=9.3,7.0Hz,2H),2.8 2(dd,J=9.4,6.5Hz,2H),1.98–1.90(m,2H),1.14(td,J=7.0,1.0Hz,6H).

[0049] Liquid mass [M+H] + m / z: calculated value 260.16, found value 260.28.

[0050] Example 2

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

[0052]

[0053] Step 1: Add 10.50 g (0.05 mol) of 6-bromoquinoline, 9.95 g (0.076 mol) of acrolein diethyl acetal, 10.65 g (0.077 mol) of potassium carbonate and 32 mL of N,N-dimethylformamide, replace the air in the three-necked flask with nitrogen, add 0.46g (0.006mol) of bistriphenylphosphine palladium dichloride under nitrogen purge, heat to 90℃ and react for 6h. After the reaction is completed under TLC monitoring, cool to room temperature, add 20mL of water and ethyl acetate respectively to the reaction system, stir for 20min, filter through diatomaceous earth, take the filtrate and let it stand for phase separation, retain the organic phase, extract the aqueous phase with ethyl acetate (20mL*2), combine the organic phases, wash with saturated brine, and concentrate under reduced pressure to obtain a crude product; the crude product is purified by 200-300 silica gel column chromatography (n-hexane: ethyl acetate = 10:1) to obtain 12.31g of yellow oily compound I with a yield of 94.8%.

[0054] 1 H NMR (400 MHz, DMSO-d 6): 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=16.1H z, 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 mass [M+H] + m / z: calculated value 258.14, found value 258.25.

[0056] Step 2: Add 5 g (0.02 mol) of the prepared 6-(3,3-diethoxyprop-1-en-1-yl)quinoline, 0.25 g of palladium on carbon and 15 mL of tetrahydrofuran to the reaction kettle in sequence, replace the air in the reaction kettle with hydrogen, react for 24 h under 0.6 atm of hydrogen, and after the reaction is completed by TLC monitoring, filter with diatomaceous earth, and concentrate the filtrate under reduced pressure to obtain a crude product; the crude product is purified by 200-300 silica gel column chromatography (n-hexane: ethyl acetate = 5:1) to obtain a yellow oil, i.e. 4.87 g of 6-(3,3-diethoxypropyl)quinoline, with a yield of 96.8%.

[0057] 1 H NMR (400 MHz, DMSO-d 6 ): 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),7.54–7.48(m,1H),4 .51(t,J=5.6Hz,1H),3.66–3.56(m,2H),3.46(dq,J=9.3,7.0Hz,2H),2.8 2(dd,J=9.4,6.5Hz,2H),1.98–1.90(m,2H),1.14(td,J=7.0,1.0Hz,6H).

[0058] Liquid mass [M+H] + m / z: calculated value 260.16, found value 260.28.

[0059] Example 3

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

[0061]

[0062] Step 1: Add 10.50 g (0.05 mol) of 6-bromoquinoline, 13.15 g (0.10 mol) of acrolein diethyl acetal, 13.96 g (0.10 mol) of potassium carbonate and 45 mL of N,N-dimethylformamide, replace the air in the three-necked flask with nitrogen, add 3.55g (0.005mol) of bistriphenylphosphine palladium dichloride under nitrogen purge, heat to 70℃ and react for 3h. After the reaction is completed under TLC monitoring, cool to room temperature, add 20mL of water and ethyl acetate respectively to the reaction system, stir for 20min, filter through diatomaceous earth, take the filtrate and let it stand for phase separation, retain the organic phase, extract the aqueous phase with ethyl acetate (20mL*2), combine the organic phases, wash with saturated brine, and concentrate under reduced pressure to obtain a crude product; the crude product is purified by 200-300 silica gel column chromatography (n-hexane: ethyl acetate = 10:1) to obtain 12.37g of yellow oily compound I with a yield of 95.3%.

[0063] 1 H NMR (400 MHz, DMSO-d 6 ): 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=16.1 Hz, 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 mass [M+H] + m / z: calculated value 258.14, found value 258.25.

[0065] Step 2: Add 5 g (0.02 mol) of the above-prepared 6-(3,3-diethoxyprop-1-en-1-yl)quinoline, 1 g of palladium on carbon and 25 mL of tetrahydrofuran to the reaction kettle in sequence, replace the air in the reaction kettle with hydrogen, react for 18 h under 0.3 atm of hydrogen, and after the reaction is completed by TLC monitoring, filter with diatomaceous earth, take the filtrate and concentrate under reduced pressure to obtain a crude product; the crude product is purified by 200-300 silica gel column chromatography (n-hexane: ethyl acetate = 5:1) to obtain a yellow oil, i.e. 4.74 g of 6-(3,3-diethoxypropyl)quinoline, with a yield of 94.2%.

[0066] 1H NMR (400 MHz, DMSO-d 6 ): 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),7.54–7.48(m,1H),4 .51(t,J=5.6Hz,1H),3.66–3.56(m,2H),3.46(dq,J=9.3,7.0Hz,2H),2.8 2(dd,J=9.4,6.5Hz,2H),1.98–1.90(m,2H),1.14(td,J=7.0,1.0Hz,6H).

[0067] Liquid mass [M+H] + m / z: calculated value 260.16, found value 260.28.

[0068] Comparative Example 1

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

[0070] 10.50g (0.05mol) 6-bromoquinoline, 10.51g (0.08mol) acrolein diethyl acetal, 12.56g (0.09mol) potassium carbonate, and 21mL N,N-dimethylformamide were added to a 100mL three-necked flask in sequence, the air in the three-necked flask was replaced with nitrogen, 2.31g (0.002mol) tetrakistriphenylphosphine palladium was added under nitrogen purge, the temperature was raised to 80°C and reacted for 16h, and no obvious product point was observed by TLC monitoring. This proves that tetrakistriphenylphosphine palladium cannot catalyze the Heck coupling reaction of 6-bromoquinoline and acrolein diethyl acetal.

[0071] Comparative Example 2

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

[0073] 10.50g (0.05mol) 6-bromoquinoline, 10.51g (0.08mol) acrolein diethyl acetal, 12.56g (0.09mol) potassium carbonate, and 21mL N,N-dimethylformamide were added to a 100mL three-necked flask in sequence, the air in the three-necked flask was replaced with nitrogen, 0.74g (0.002mol) triphenylphosphine palladium was added under nitrogen purge, the temperature was raised to 80°C and reacted for 16h, and no obvious product point was observed by TLC monitoring. This proves that triphenylphosphine palladium cannot catalyze the Heck coupling reaction of 6-bromoquinoline and acrolein diethyl acetal.

[0074] Comparative Example 3

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

[0076] 10.50g (0.05mol) 6-bromoquinoline, 10.51g (0.08mol) acrolein diethyl acetal, 12.56g (0.09mol) potassium carbonate, and 21mL N,N-dimethylformamide were added to a 100mL three-necked flask in sequence, the air in the three-necked flask was replaced with nitrogen, 2.3g palladium carbon was added under nitrogen purge, the temperature was raised to 80°C and reacted for 16h, and no obvious product point was observed by TLC monitoring. This proves that palladium carbon catalyst cannot catalyze the Heck coupling reaction of 6-bromoquinoline and acrolein diethyl acetal.

[0077] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for synthesizing a capmatinib intermediate 6-(3,3-diethoxypropyl)quinoline, characterized in that: The steps include: S1, under alkaline conditions, using bistriphenylphosphine palladium dichloride as a catalyst, 6-bromoquinoline and acrolein diethyl acetal undergo Heck coupling reaction to obtain compound Ⅰ; S2, subjecting compound I to hydrogenation reduction reaction to obtain 6-(3,3-diethoxypropyl)quinoline.

2. The method for synthesizing the capmatinib intermediate 6-(3,3-diethoxypropyl)quinoline according to claim 1, characterized in that: The specific steps include: Step 1, 6-bromoquinoline, propylene acetal diethanol and a base are added to a first solvent, and bistriphenylphosphine palladium dichloride is added under an inert atmosphere to carry out a Heck coupling reaction to obtain compound I; Step 2: Add compound I and a catalyst into a 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 capmatinib intermediate 6-(3,3-diethoxypropyl)quinoline according to claim 2, characterized in that: In step 1, the first solvent is N,N-dimethylformamide; and / or In step 1, the base is potassium carbonate.

4. The method for synthesizing the capmatinib intermediate 6-(3,3-diethoxypropyl)quinoline according to claim 2, characterized in that: In step 2, the catalyst is a palladium-carbon catalyst; and / or In step 2, the second solvent is tetrahydrofuran.

5. The method for synthesizing the capmatinib intermediate 6-(3,3-diethoxypropyl)quinoline according to claim 2, characterized in that: In step 1, the molar ratio of 6-bromoquinoline, acrolein diethyl acetal, bistriphenylphosphine palladium dichloride and base is 1:(1.5-2):(0.01-0.1):(1.5-2).

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

7. The method for synthesizing the capmatinib intermediate 6-(3,3-diethoxypropyl)quinoline according to claim 2, characterized in that: In step 1, the temperature of the Heck coupling reaction is 70° C. to 90° C., and the reaction time is 3 h to 6 h.

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

9. The method for synthesizing the capmatinib intermediate 6-(3,3-diethoxypropyl)quinoline according to claim 2, characterized in that: In step 2, the temperature of the hydrogenation reduction reaction is 10° C. to 40° C., the reaction pressure is 0.3 atm to 1 atm, and the reaction time is 18 h to 24 h.

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

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