CN116410159B

CN116410159B - Preparation method and application of En Qu Ti-Ni intermediate

Info

Publication number: CN116410159B
Application number: CN202310679953.4A
Authority: CN
Inventors: 周军民; 李淑娴; 马崇雷; 贺俊华; 时东旭; 韩超
Original assignee: Jinan Guoding Pharmaceutical Technology Co ltd
Current assignee: Jinan Guoding Pharmaceutical Technology Co ltd
Priority date: 2023-06-09
Filing date: 2023-06-09
Publication date: 2023-08-22
Anticipated expiration: 2043-06-09
Also published as: CN116410159A

Abstract

The application discloses a preparation method and application of an En Qu Ti-Ni intermediate, belonging to the technical field of compound reaction, and comprising the following steps: adding 4-fluoro-2-nitrobenzoic acid into a reaction container, dissolving by using a solvent, adding N-methylpiperazine under stirring, controlling the reaction temperature to be 80-100 ℃, and performing rotary evaporation after the reaction is finished; step two, adding solvent, pyridine, tertiary butanol and phosphorus oxychloride, reacting at room temperature, spin drying after the reaction is finished, adding water for crystallization, and obtaining the 2-nitro-4- (4-methyl-1-piperazine) tert-butyl benzoate. The application provides a process for reacting 4-fluoro-2-nitrobenzoic acid with N-methylpiperazine and then esterifying, which does not need to add di-tert-butyl methyl dicarbonate, thereby reducing the usage amount of N-methylpiperazine; the consumption of the solvent is reduced, and the dangerous waste is reduced; the method has the advantages of high reaction speed, short reaction time, simple post-treatment process, shortened production period and reduced energy consumption.

Description

Preparation method and application of En Qu Ti-Ni intermediate

Technical Field

The application relates to the technical field of compound reaction, in particular to a preparation method and application of an En Qu Ti Ni intermediate.

Background

Entrictinib is a potent and selective inhibitor of central nervous system activity targeting TRK (tropomyosin receptor kinase) and ROS1 (a receptor tyrosine kinase encoded), is capable of crossing the blood brain barrier, is the only TRK inhibitor clinically proven to be therapeutic against primary and metastatic brain diseases, and has no undesirable off-target activity; can block ROS1, ALK and NTRK kinase activity and may result in cancer cell death of ROS1, ALK or NTRK gene fusion. In month 8 2019, the U.S. FDA announced that the new drug emtrictinib of rocarvensis was marketed for the treatment of adult and pediatric patients with advanced recurrent solid tumors positive for NTRK gene fusion mutations. Meanwhile, emtrictinib is approved by FDA for treating metastatic non-small cell lung cancer carrying ROS1 gene mutation. In 2022, 7 months, emtrictinib was marketed in the domestic batch, and the first indication was that patients with locally advanced or metastatic solid tumors positive for NTRK fusion genes were the first ROS1 inhibitor in the country with clear central nervous system efficacy. Only after two weeks, the second indication of emtrictinib was approved for treatment of ROS1 positive advanced non-small cell lung cancer.

However, the price of the present En Qu Ti is very expensive, and in order to reduce the production cost of the En Qu Ti, it is particularly important to develop an En-qu-tinib synthetic route which is economical and environment-friendly and is suitable for industrial production.

Tert-butyl 2-nitro-4- (4-methyl-1-piperazine) benzoate is used as a key intermediate for preparing emtrictinib, and the synthesis research of the tert-butyl 2-nitro-4- (4-methyl-1-piperazine) benzoate is important. The most published synthetic routes for tert-butyl 2-nitro-4- (4-methyl-1-piperazine) benzoate are currently: the method is characterized in that 4-fluoro-2-nitrobenzoic acid is taken as a raw material, esterified and then reacted with N-methylpiperazine, specifically, 4-fluoro-2-nitrobenzoic acid is subjected to esterification reaction with tert-butyl alcohol under the action of di-tert-butyl methyl dicarbonate and 4-dimethylaminopyridine, and then subjected to nucleophilic substitution reaction with N-methylpiperazine. The reaction equation is as follows:

according to the information disclosed in Liu Yan et al, in the article "synthesis process optimization of anti-tumor drug emtrictinib" published in chemical reagent 42, the first-step reaction yield is 75.2%, the second-step yield is 87.9%, the total yield is 66.1%, and the purity of the intermediate is not marked; the publication "indazoles and compositions and uses thereof for inhibiting kinase activity" (publication No. CN 108623576) indicates that the first step yield in this process is 53.7%, the second step yield is 74.5%, the total yield is 40.0%, and the purity of the intermediate is not indicated; patent "HETEROCYCLIC DERIVATIVES MODULATING ACTIVITY OF CERTAIN PROTEIN KINASES" (application number: WO2016096709A 1) discloses that the first step yield of the process is 86%, the second step yield is 95%, the total yield is 81.7%, and the purity of the intermediate is not indicated.

The reaction time of the first step in the method is longer (more than 24 hours), and the post-treatment needs quenching, acid washing, water washing and steaming reduction, and the steps have mild operation conditions, but the process has more procedures, so that the production period is long and the energy consumption is high; in addition, the first reaction step has a relatively large amount of di-t-butyl methyl dicarbonate remaining, and the remaining di-t-butyl methyl dicarbonate affects the next reaction step, and an equivalent amount of N-methylpiperazine is consumed during the reaction, resulting in an increase in the amount of N-methylpiperazine. In the second step of the method, N-dimethylformamide is used as a solvent, water is adopted for crystallization during crystallization, so that waste liquid is difficult to treat, and the environmental burden is high. The above problems lead to a great increase in the production cost of the tert-butyl 2-nitro-4- (4-methyl-1-piperazine) benzoate, and are also unfavorable for safe industrial production.

Disclosure of Invention

Aiming at the problems existing in the prior art, the application provides a method for preparing the En Qu Ti nylon intermediate by reacting 4-fluoro-2-nitrobenzoic acid with N-methylpiperazine at a higher temperature and esterifying the N-nitrobenzoic acid with N-methylpiperazine.

In the prior art, the steps of esterifying 4-fluoro-2-nitrobenzoic acid and then reacting with N-methylpiperazine are mostly adopted, and the method is characterized in that the whole process adopts room temperature, the reaction condition is mild, and the 4-fluoro-2-nitrobenzoic acid and the N-methylpiperazine cannot react directly at room temperature, so that the technical improvement of the prior art is limited.

Analyzing the mechanism, the reaction is basically electrophilic reaction, and adopts a reagent with electron deficiency to attack a region with higher electron cloud density (electron rich) of another compound to cause the reaction, the higher the electron cloud density on a benzene ring is, the more beneficial to the reaction, and according to the thought, the prior art firstly carries out esterification reaction to protect carboxyl, so that the electron-withdrawing effect of the carboxyl is reduced, and the substitution of N-methylpiperazine is further facilitated.

However, during the research of the skilled person, it was found that the substitution scheme of N-methylpiperazine provided by the present application was used, although the reaction conditions would need to be enhanced, e.g. room temperature was raised above 80℃to a degree that is easy to realize industrially. But the advantages are unexpected, including simplifying the post-reaction treatment steps and reducing the use amount of N-methylpiperazine; meanwhile, continuous production of multi-step reaction can be realized; the method can achieve 98 percent of yield and 99.8 percent of purity of the product.

The first aspect of the application provides a preparation method of an En Qu Ti-Ni intermediate, which comprises the following steps: in a solvent, 4-fluoro-2-nitrobenzoic acid reacts with N-methylpiperazine at 80-100 ℃, and then the intermediate of En Qu Ti is obtained by esterification. The reaction equation provided by the application is as follows:

the preparation method of the En Qu Ti Ni intermediate provided by the application comprises the following steps:

adding 4-fluoro-2-nitrobenzoic acid into a reaction container, dissolving by using a solvent, adding N-methylpiperazine under stirring, controlling the reaction temperature to be 80-100 ℃, and performing rotary evaporation after the reaction is finished;

and step two, adding a solvent, pyridine, tertiary butanol and phosphorus oxychloride into the reaction product of the step one, reacting at room temperature, spin-drying after the reaction is finished, adding water for crystallization, and obtaining the 2-nitro-4- (4-methyl-1-piperazine) benzoic acid tertiary butyl ester.

As a preferred embodiment of the present application, in the first step, 4-fluoro-2-nitrobenzoic acid is reacted with N-methylpiperazine at a temperature ranging from 80 to 85 ℃.

Further, in the first step, 4-fluoro-2-nitrobenzoic acid is reacted with N-methylpiperazine at a temperature of 85 ℃.

As a preferable technical scheme of the application, the molar ratio of the 4-fluoro-2-nitrobenzoic acid, the N-methylpiperazine, the pyridine, the tertiary butanol and the phosphorus oxychloride is 1 (1-3): 6-15): 5-10): 1-5, and under the condition of the ratio, higher yield and purity can be obtained.

As a more preferable technical scheme of the application, the molar ratio of the 4-fluoro-2-nitrobenzoic acid, the N-methylpiperazine, the pyridine, the tertiary butanol and the phosphorus oxychloride is 1:2.5:12:7:2.5. The intermediate in the first step is not taken out, the yield is calculated as 99%, the yield of the intermediate in the second step is 99%, the total yield reaches 98%, and the purity is 99.8%.

As a preferred embodiment of the present application, the solvent is selected from one or a combination of several of N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile and dichloromethane.

As a preferable technical scheme of the application, the solvent in the first step is acetonitrile, and the solvent in the second step is dichloromethane. The first step adopts acetonitrile as a solvent, so that the reaction temperature can be reached, and the obtained rotary evaporation material can be well distilled out, and the obtained rotary evaporation material can be directly used for the next step, and is more convenient compared with the original route adopting N, N-dimethylformamide. And in the second step, dichloromethane is used as a solvent, so that the reaction can be normally carried out, multiple extraction and liquid separation washes in post-treatment are omitted, and the post-treatment process is simplified.

As a preferred embodiment of the present application, the weight ratio of the solvent to 4-fluoro-2-nitrobenzoic acid in the first step is (5-10): 1.

In one embodiment of the present application, the preparation method of the intermediate of En Qu Ti comprises: adding 4-fluoro-2-nitrobenzoic acid into a reaction container, dissolving by using a solvent, adding N-methylpiperazine under stirring, controlling the reaction temperature at 80-85 ℃, carrying out thin layer chromatography to track the reaction progress, after the reaction is finished, carrying out rotary evaporation, adding dichloromethane, pyridine and tertiary butyl alcohol, phosphorus oxychloride, carrying out room temperature reaction, carrying out thin layer chromatography to track the reaction progress, carrying out rotary drying, and adding water to carry out crystallization to obtain the 2-nitro-4- (4-methyl-1-piperazine) benzoic acid tertiary butyl ester.

In a second aspect, the application provides an application of the preparation method of the En Qu Ti-Ni intermediate in preparation of Entrictinib. The method provided by the application is applied to the preparation process of the emtrictinib, so that the production period is obviously shortened, the material consumption and the cost are reduced, and the industrial production of the emtrictinib is facilitated.

Compared with the prior art, the application has the beneficial effects that:

1. according to the esterification process after the reaction with the N-methylpiperazine, the addition of the protective agent di-tert-butyl methyl dicarbonate is not needed, the unnecessary consumption of the N-methylpiperazine caused by the residue of the protective agent di-tert-butyl methyl dicarbonate is avoided, and the material consumption is reduced; the amount of the solvent is reduced, so that the hazardous waste amount is reduced, and the method is environment-friendly;

2. the method has the advantages that the reaction speed is high, the better yield can be obtained after the reaction time is not more than 20 hours, and meanwhile, the post-treatment process is simple, so that the production period is shortened, and the energy consumption is reduced;

3. the method has high selectivity, total yield up to 98% and less side reaction; the purity of the obtained product is high and can reach 99.8%, so that the quality of the product is greatly improved;

4. the method is a single solvent after the reaction is finished, and can be recycled, so that repeated extraction, liquid separation and washing in post-treatment are avoided, the environmental burden is reduced, and the industrial production is easier to realize.

Drawings

The accompanying drawings, which are included to provide a further understanding of the application and are incorporated in and constitute a part of this specification, illustrate embodiments of the application and together with the description serve to explain the application.

FIG. 1 is a hydrogen spectrum of tert-butyl 2-nitro-4- (4-methyl-1-piperazine) benzoate obtained in example 4 of the present application;

FIG. 2 is a mass spectrum of tert-butyl 2-nitro-4- (4-methyl-1-piperazine) benzoate obtained in example 4 of the present application;

FIG. 3 is a liquid phase diagram of tert-butyl 2-nitro-4- (4-methyl-1-piperazine) benzoate obtained in example 4 of the present application.

Detailed Description

It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the application. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

The liquid phase detection method comprises the following steps:

chromatographic column: welchrom C18.times.4.6 mm,5 μm column or equivalent column; flow rate: 1.0ml per minute; detection wavelength: 242nm; column temperature: 30 ℃; concentration: 0.1mg/ml; a diluent: acetonitrile H ₂ O=1:9, acetonitrile was added first to dissolve, and then water was used to fix the volume.

The following gradient was performed:

time (minutes)	Mobile phase a (0.1% TFA in H ₂ O）	Mobile phase B (acetonitrile)
			0	95	5
15	5	95
			20	5	95
20.1	95	5
			25	95	5

Example 1

The embodiment 1 of the application provides a preparation method of an En Qu Ti-Ni intermediate, which comprises the following steps:

in a 2L three-necked flask, 4-fluoro-2-nitrobenzoic acid (100.0 g,0.54 mol), N-methylpiperazine (81.1 g,0.81 mol) and acetonitrile are added, the temperature is raised to 80 ℃, the reaction progress is followed by thin layer chromatography, the reaction is carried out for 6h, the reaction is carried out by spin-drying, 1000ml of dichloromethane, 424.7ml of tertiary butanol, 181.7ml of pyridine and 76.2ml of phosphorus oxychloride are added, the reaction is carried out at room temperature, the reaction is carried out by thin layer chromatography, the reaction is carried out for 12h, the spin-drying is carried out, water crystallization is added, 156.24g of target product 2-nitro-4- (4-methyl-1-piperazine) benzoic acid tert-butyl ester is obtained by filtration, the total yield is 90.0%, and the purity is 98.4%.

Example 2

The embodiment 2 of the application provides a preparation method of an En Qu Ti-Ni intermediate, which comprises the following steps:

in a 2L three-necked flask, 4-fluoro-2-nitrobenzoic acid (100.0 g,0.54 mol), N-methylpiperazine (108.2 g,1.08 mol) and acetonitrile were added, heated to 85 ℃, followed by thin layer chromatography for reaction for 6h, spin-drying, adding dichloromethane (900 ml), tert-butanol (504.3 ml), pyridine (249.8 ml) and phosphorus oxychloride (102 ml), reacting at room temperature, followed by thin layer chromatography for reaction for 12h, spin-drying, adding water for crystallization, and filtering to obtain the target product tert-butyl 2-nitro-4- (4-methyl-1-piperazine) benzoate (161.4 g), with a total yield of 93.0% and a purity of 99.0%.

Example 3

The embodiment 3 of the application provides a preparation method of an En Qu Ti-Ni intermediate, which comprises the following steps:

in a 2L three-necked flask, 4-fluoro-2-nitrobenzoic acid (100.0 g,0.54 mol), N-methylpiperazine (135 g,1.35 mol) and acetonitrile 550ml are added, the temperature is heated to 85 ℃, the reaction progress is tracked by thin layer chromatography, the reaction is carried out for 6 hours, the mixture is dried by spinning, dichloromethane 700ml, tert-butanol 583.9ml, pyridine 272.5ml and phosphorus oxychloride 107ml are added, the reaction is carried out for 12 hours at room temperature, the reaction is carried out for 12 hours, the mixture is dried by spinning after the reaction, water crystallization is added, and the mixture is filtered to obtain the target product, namely 164.9g of tert-butyl 2-nitro-4- (4-methyl-1-piperazine) benzoate, the total yield is 95.0%, and the purity is 99.5%.

Example 4

The embodiment 4 of the application provides a preparation method of an En Qu Ti-Ni intermediate, which comprises the following steps:

in a 2L three-necked flask, 4-fluoro-2-nitrobenzoic acid (100.0 g,0.54 mol), N-methylpiperazine (135 g,1.35 mol) and acetonitrile 550ml are added, the temperature is heated to 85 ℃, the reaction progress is tracked by thin layer chromatography, the reaction is carried out for 6 hours, the reaction progress is tracked by thin layer chromatography, dichloromethane 700ml, tert-butanol 637ml, pyridine 318ml and phosphorus oxychloride 127ml are added, the reaction is carried out for 12 hours at room temperature, the reaction progress is tracked by thin layer chromatography, the reaction is carried out for 12 hours, water is added for crystallization, and the target product of 170.1g of tert-butyl 2-nitro-4- (4-methyl-1-piperazine) benzoate is obtained by filtration, the total yield is 98.0%, and the purity is 99.9%.

The hydrogen spectrum and mass spectrum of the obtained product are shown in fig. 1 and 2, and the mass spectrum and hydrogen spectrum data are as follows:

MS：322［M+H］；

¹ H NMR (400 MHz, DMSO-d ⁶ )，ppm：7.73 (dd, J = 8.8, 1.5 Hz, 1H), 7.03 – 6.92 (m, 2H), 3.37 (t, J = 5.1 Hz, 4H), 2.56 (t, J = 5.0 Hz, 4H), 2.37 (d, J = 1.5 Hz, 3H), 1.54 (s, 9H)。

the liquid phase detection results are shown in the following table and fig. 3, and the intermediate product of the application, namely the En Qu Ti Ni, has fewer impurities and higher purity.

Sequence number	Retention time[min]	Peak height [ mAU]	Peak height [%]	Peak area [ mAU.s]	Peak area [%]	Peak width at peak height of 0.05 [ min]
							1	10.545	6.104	0.30	14.148	0.1206	0.059
2	11.924	2025.322	99.70	11719.602	99.8794	0.191
							Totalizing		2031.426	100.00	11733.750	100.0000

Example 5

The embodiment 5 of the application provides a preparation method of an En Qu Ti-Ni intermediate, which comprises the following steps:

in a 2L three-necked flask, 4-fluoro-2-nitrobenzoic acid (100.0 g,0.54 mol), N-methylpiperazine (124.2 g,1.242 mol) and acetonitrile are added, the temperature is raised to 85 ℃, the reaction progress is tracked by thin layer chromatography, the reaction is carried out for 6 hours, the reaction progress is tracked by spin-drying, dichloromethane (700 ml), tert-butanol (557.4 ml), pyridine (227 ml) and phosphorus oxychloride (116.84 ml) are added, the reaction is carried out for 12 hours at room temperature, the reaction progress is tracked by thin layer chromatography, the spin-drying is carried out after the reaction for 12 hours, water crystallization is added, 166.6g of tert-butyl 2-nitro-4- (4-methyl-1-piperazine) benzoate is obtained by filtration, the total yield is 96.0%, and the purity is 98.9%.

Example 6

The embodiment 6 of the application provides a preparation method of an En Qu Ti-Ni intermediate, which comprises the following steps:

in a 2L three-necked flask, 4-fluoro-2-nitrobenzoic acid (100.2 g,0.54 mol), N-methylpiperazine (124 g,1.242 mol) and N, N-dimethylformamide (550 ml) are added, the reaction progress is followed by heating to 100 ℃, thin layer chromatography, the reaction is carried out for 10h, N-dimethylformamide is removed by reduced pressure rotary evaporation, then 700ml of dichloromethane, 558ml of tert-butanol, 228ml of pyridine and 116ml of phosphorus oxychloride are added, the reaction is carried out for 12h at room temperature, the reaction progress is followed by rotary drying after 12h, water crystallization is added, and the filtration is carried out to obtain 163.5g of the target product, namely, tert-butyl 2-nitro-4- (4-methyl-1-piperazine) benzoate, the total yield is 94.2%, and the purity is 99.2%.

Comparative example 1

The same materials as in example 4 were used, except that after 4-fluoro-2-nitrobenzoic acid, N-methylpiperazine and acetonitrile were added, the mixture was heated to 50℃and the progress of the reaction was followed by thin layer chromatography, followed by spin-drying, methylene chloride, t-butanol, pyridine and phosphorus oxychloride were added, the reaction was carried out at room temperature for 12 hours, followed by spin-drying after 12 hours, water was added for crystallization, and 102.3g of the target product t-butyl 2-nitro-4- (4-methyl-1-piperazine) benzoate was obtained by filtration, with a total yield of 58.9% and a purity of 99.3%.

Comparative example 2

The same materials as in example 4 were used, except that after 4-fluoro-2-nitrobenzoic acid, N-methylpiperazine and acetonitrile were added, the mixture was heated to 50℃and the progress of the reaction was followed by thin layer chromatography, the mixture was subjected to a reaction for 18 hours, spin-drying, methylene chloride, t-butanol, pyridine and phosphorus oxychloride were added, the reaction was carried out at room temperature for 12 hours, the reaction was followed by thin layer chromatography, the spin-drying was carried out after the reaction for 12 hours, water was added to crystallize, and 123.1g of the target product t-butyl 2-nitro-4- (4-methyl-1-piperazine) benzoate was obtained by filtration, the total yield was 70.9%, and the purity was 89.9%.

As is clear from comparative examples 1 and 2, the yield of the obtained product was lowered after lowering the reaction temperature of the first step, and the analysis was conducted because the reaction temperature of the first step was low, the reaction was incomplete, the yield could not be raised to a large extent even if the reaction time was prolonged, and the purity of the product obtained by the same post-treatment method was lowered as the reaction time was prolonged.

The foregoing examples are illustrative only and serve to explain some features of the method of the application. The appended claims are intended to claim the broadest possible scope and the embodiments presented herein are merely illustrative of selected implementations based on combinations of all possible embodiments. It is, therefore, not the intention of the applicant that the appended claims be limited by the choice of examples illustrating the features of the application. Some numerical ranges used in the claims also include sub-ranges within which variations in these ranges should also be construed as being covered by the appended claims where possible.

Claims

1. The preparation method of the En Qu Ti nylon intermediate is characterized by comprising the following steps of:

adding 4-fluoro-2-nitrobenzoic acid into a reaction container, dissolving by using a solvent, adding N-methylpiperazine under stirring, controlling the reaction temperature to be 80-85 ℃, and performing rotary evaporation after the reaction is finished;

step two, adding a solvent, pyridine, tertiary butanol and phosphorus oxychloride into the reaction product of the step one, reacting at room temperature, spin-drying after the reaction is finished, adding water for crystallization, and obtaining the 2-nitro-4- (4-methyl-1-piperazine) benzoic acid tertiary butyl ester;

the molar ratio of the 4-fluoro-2-nitrobenzoic acid to the N-methylpiperazine to the pyridine to the tertiary butanol to the phosphorus oxychloride is 1 (1-3): (6-15): (5-10): (1-5);

the solvent in the first step is acetonitrile, and the solvent in the second step is dichloromethane.

2. The process for preparing an intermediate of en Qu Ti according to claim 1, wherein in step one, 4-fluoro-2-nitrobenzoic acid is reacted with N-methylpiperazine at a temperature of 85 ℃.

3. The method for preparing the intermediate of the En Qu Ti nylon according to claim 1, wherein the molar ratio of the 4-fluoro-2-nitrobenzoic acid, the N-methylpiperazine, the pyridine, the tertiary butanol and the phosphorus oxychloride is 1:2.5:12:7:2.5.

4. The process for preparing an En Qu Ti Ni intermediate according to claim 1, wherein the weight ratio of the solvent to 4-fluoro-2-nitrobenzoic acid in the first step is (5-10): 1.

5. The method for preparing an en Qu Ti intermediate according to claim 1, comprising: adding 4-fluoro-2-nitrobenzoic acid into a reaction container, dissolving by using a solvent, adding N-methylpiperazine under stirring, controlling the reaction temperature at 80-85 ℃, carrying out thin layer chromatography to track the reaction progress, after the reaction is finished, carrying out rotary evaporation, adding dichloromethane, pyridine and tertiary butyl alcohol, phosphorus oxychloride, carrying out room temperature reaction, carrying out thin layer chromatography to track the reaction progress, carrying out rotary drying, and adding water to carry out crystallization to obtain the 2-nitro-4- (4-methyl-1-piperazine) benzoic acid tertiary butyl ester.

6. The use of the method for preparing an en Qu Ti nylon intermediate according to any one of claims 1 to 5 in the preparation of entrictinib.