CN111825678A

CN111825678A - Preparation method of carbamatinib

Info

Publication number: CN111825678A
Application number: CN202010507179.5A
Authority: CN
Inventors: 连庆泉
Original assignee: Individual
Current assignee: Individual
Priority date: 2020-06-05
Filing date: 2020-06-05
Publication date: 2020-10-27

Abstract

The invention provides a preparation method of carbamatinib, and the inventor conducts extensive and intensive research, and obtains a compound shown in a formula I, namely the carbamatinib, by taking a compound shown in a formula III as a raw material through hydrolysis reaction and methylation reaction through a large number of screening and testing. The method has the advantages of mild reaction conditions, environmental friendliness, low energy consumption, good product purity and high yield, and is suitable for industrial mass production.

Description

Preparation method of carbamatinib

Technical Field

The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of carbamatinib.

Background

Carbamatinib (INC280) is a METex14 inhibitor developed by novartis, switzerland for metastatic non-small cell lung cancer (NSCLC) patients carrying MET exon 14 skipping mutations, including first line (treatment-naive) patients and patients who have previously received treatment (treated).

NSCLC accounts for approximately 85% of lung cancer diagnoses. The METex14 mutation occurs in 3-4% of newly diagnosed advanced NSCLC cases, a lung cancer with a very poor prognosis, and there is currently no approved therapy for advanced NSCLC with the METex14 mutation.

On day 11/2/2020, the FDA received a New Drug Application (NDA) for the MET inhibitor capmatib (INC280) and granted priority, evaluating its application to metastatic non-small cell lung cancer (NSCLC) patients, including first line (naive) patients and previously treated (treated) patients, carrying a MET exon 14 skipping mutation.

This priority approval was based on positive results from phase II clinical study geodetry mono-1, with 97 patients enrolled:

(1) in naive patients (28, not previously treated), total remission rate (ORR) was 67.9%, Disease Control Rate (DCR) was 96.4%, median duration of remission (DOR) was 11.14 months, median progression-free survival was 9.69 months;

(2) in treated patients (69, previously treated, 88.4% platinum-containing chemotherapy), the Overall Remission Rate (ORR) was 40.6%, the Disease Control Rate (DCR) was 78.3%, the median duration of remission (DOR) was 9.72 months, and the median progression-free survival was 5.42 months;

(3) approximately half of patients with brain metastases responded to caplatinib (7 out of 13; 54%). Of these patients, 4 completely eliminated brain lesions (31%), with an intracranial Disease Control Rate (DCR) of 92.3% (12/13).

If approved, carbamatinib would be the second therapeutic specific for the METex14 mutant advanced lung cancer. The chemical name of the carbamatinib is 2-fluoro-N-methyl-4- [7- [ (quinoline-6-yl) methyl ] imidazo [1,2-B ] - [1,2,4] triazine-2-yl ] benzamide, and the structure is shown as the formula I:

a process for the preparation of carbamatinib is disclosed in US2009291956a1, which comprises the following synthetic route:

the amidation reaction in the original research process converts the compound III into 2-fluoro-N-methyl-4- [7- [ (quinoline-6-yl) methyl ] imidazo [1,2-B ] - [1,2,4] triazine-2-yl ] benzoic acid, and the reaction needs to be carried out under strong acidity and high temperature, so that a series of problems of high energy consumption, high equipment corrosiveness, high environmental protection pressure and the like exist in industrial production. Therefore, it is urgently needed to develop a synthesis process more suitable for industrial production.

Disclosure of Invention

In order to overcome the problems in the prior art, the invention provides a preparation method of carbamatinib, namely a compound of formula I, which comprises the following steps:

step (1): subjecting the compound of formula iii to hydrolysis to obtain a compound of formula ii:

step (2): methylating a compound of formula ii to provide a compound of formula i:

according to an embodiment of the present invention, the hydrolysis reaction in step (1) may be performed by reacting the compound of formula iii with 30% hydrogen peroxide under alkaline conditions and in the presence of a catalyst to produce a compound of formula ii; preferably, the catalyst is selected from the group consisting of: tetramethylammonium chloride, tetraethylammonium chloride, tetrabutylammonium bromide, hexadecyltrimethylammonium bromide, benzyltriethylammonium chloride, or a combination of one, two or more thereof.

According to an embodiment of the invention, the weight-to-volume ratio (g/ml) of the compound of formula III in the step (1) and 30% hydrogen peroxide can be 1 (10-50), such as 1 (15-40) or 1 (20-30).

According to an embodiment of the present invention, the hydrolysis reaction of step (1) may be carried out in a first solvent immiscible with water; preferably, the first solvent is selected from: ethyl acetate, dichloromethane, dichloroethane, chloroform, toluene, xylene, or a combination of one, two or more thereof.

According to an embodiment of the present invention, the alkaline conditions of the hydrolysis reaction of step (1) may be provided by the following reagents: sodium hydroxide, potassium hydroxide, lithium hydroxide, or a combination of one, two or three thereof.

According to an embodiment of the present invention, the reaction temperature of the hydrolysis reaction of step (1) may be 0 to 30 ℃, for example, room temperature, such as 20 to 25 ℃.

According to an embodiment of the present invention, the methylation reaction of step (2) may be carried out in a second solvent; preferably, the second solvent is selected from: n, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, acetone, acetonitrile, tetrahydrofuran, or a combination of one, two or more thereof.

According to an embodiment of the invention, the methylation reaction of step (2) is carried out in the presence of a strongly basic reagent, suitably a strongly basic reagent selected from: sodium hydroxide, sodium methoxide, sodium amide, sodium hydride, n-butyl lithium, lithium diisopropylamide, or a combination of one, two or more thereof.

According to an embodiment of the present invention, the methylating agent of step (2) may be selected from: dimethyl sulfate, methyl iodide, dimethyl carbonate, monochloromethane and 1-methoxy-2, 2,6, 6-tetramethyl piperidine.

According to an embodiment of the present invention, the molar ratio of the compound of formula II in step (2) to the methylating agent may be 1 (1-10), such as 1 (1-8), 1 (1-5) or 1 (1-3).

According to an embodiment of the present invention, the reaction temperature of the methylation reaction of step (2) may be 20 to 90 ℃, such as 30 to 80 ℃ or 40 to 70 ℃, exemplary 60 ℃.

According to an embodiment of the invention, the compounds of formula III may be obtained by methods known in the literature (e.g. US 20090291956a1) or may be synthesized by the skilled person on the basis of his knowledge of organic chemistry, using suitable starting materials.

Advantageous effects

The inventor conducts extensive and intensive research, and obtains the compound of the formula I, namely the carbamatinib by taking the compound of the formula III as a raw material through hydrolysis reaction and methylation reaction through a large amount of screening and testing. The method has the advantages of mild reaction conditions, environmental friendliness, low energy consumption, good product purity and high yield, and is suitable for industrial mass production. The invention has the advantages that the yield and the purity of the methylation reaction of the compound shown in the formula II are superior to those of the amidation reaction in the prior art. By choosing the mature hydrolysis and methylation protocol, a total yield of 79.2% was achieved, whereas the original hydrolysis and amidation reactions, a total yield of 72.9%, were achieved. Moreover, the purity of the product obtained in each step of the method is very high, the purity of the intermediate obtained in the step 1 is 98.5 percent, the purity of the final product obtained in the step 2 is 99.5 percent, the purity basically meets the requirement of medicinal purity, and no more complicated purification steps can be performed. The invention has the advantages of low equipment loss, low energy consumption, low environmental protection pressure and capability of effectively reducing the production cost.

Detailed Description

The preparation method of carbamatinib according to the present invention will be described in further detail with reference to specific examples. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.

Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.

Example 1 preparation of carbamatinib

Step 1: formula IIPreparation of the Compounds

38.2g (0.1mol) of the compound of formula III, dichloromethane 200ml and water 100ml are added into a 2L reaction bottle, then, 2g of tetrabutylammonium chloride, 150ml of 30% hydrogen peroxide and 200ml of 20% sodium hydroxide aqueous solution are reacted for 5 to 6 hours at room temperature, 100ml of dichloromethane is added after the reaction is finished, the mixture is stirred and separated, the dichloromethane phase is washed once by sodium sulfite aqueous solution, washed once by clear water and concentrated to dryness by dichloromethane, and 35.1g of the title compound is obtained with the yield of 88% and the HPLC purity of 98.5%. Ms (esi): and M +1 is 399.5.

Step 2:preparation of carbamatinib

Adding 500ml of DMF and 20.0g (0.05mol) of the compound of the formula II into a 2L reaction bottle, stirring for dissolving, cooling to 0-5 ℃, adding 2.4g (0.06mol) of 60% sodium hydride in mineral oil in batches, stirring for 0.5 hour after the addition is finished, dropwise adding 7.5g (0.06mol) of dimethyl sulfate, completing the dropwise addition, and slowly raising the temperature to 60 ℃ for reacting for 2 hours. After the reaction was completed, diluted hydrochloric acid was added dropwise to quench, part of the solvent was concentrated under reduced pressure, poured into water, extracted with ethyl acetate, the aqueous phase was made alkaline, extracted with ethyl acetate, washed with water, and the organic phase was concentrated to give 18.6g of a yellow solid, which was the title compound, in 90% yield and 99.5% purity by HPLC. Ms (esi): [ M +1]]＝412.9。¹H-NMR(400MHz,DMSO-d6):9.20(1H，s)，8.82(1H，dd)，8.38(1H，m)，8.27(1H，dd)，8.06-7.93(5H，m)，7.81-7.74(2H，m)，7.49(1H，dd)，4.62(2H，s)，2.78(3H，d)。

Comparative example 1 preparation of carbamatinib (cf. US2009291956A1, examples 19 and 20)

First, referring to example 19 of US2009291956a1, 2-fluoro-N-methyl-4- [7- [ (quinolin-6-yl) methyl ] imidazo [1,2-B ] - [1,2,4] triazin-2-yl ] benzoic acid is prepared as follows:

adding 2500ml of concentrated hydrochloric acid, 100ml of water and 277.5g (0.73mol) of the compound shown in the formula III into a 5000ml reaction bottle, stirring for dissolving, heating to 100 ℃ for refluxing for 18 hours, finishing LC-MS tracking reaction, cooling the reaction liquid to 80 ℃, transferring to a 10L stirring device, adding 2500ml of water, cooling for crystallization, continuously cooling to 0 ℃ after solid is separated out, filtering to obtain solid, washing the filter cake with 1N hydrochloric acid, and drying the solid in vacuum to obtain 262.3g of the title compound with the yield of 90%. Ms (esi): [ M +1] ═ 400.1.

Then, referring to example 20 of US2009291956a1, carbamatinib was prepared by the following specific method:

adding DMF3700ml into a 10L reaction vessel, adding 431.4g (0.914mol) of 2-fluoro-N-methyl-4- [7- [ (quinolin-6-yl) methyl ] imidazo [1,2-B ] - [1,2,4] triazin-2-yl ] benzoic acid, 570g (1.1mol) of PyBOP (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate) with stirring for dissolution, dropwise adding 1.83L (3.656mol, 4eq) of 2M methylamine-tetrahydrofuran solution at room temperature, controlling the dropwise adding time to be more than 15 minutes, increasing the temperature to 30 ℃ when dropwise adding, adding 382ml (2.742mol, 3.0eq) of triethylamine after dropwise adding, performing LC-MS tracking reaction for 2-4 hours at room temperature, adding 950ml of water after the reaction, cooling to 0 ℃, filtering the obtained product, leaching once with 200ml of water, the wet product was stirred for 1 hour with 2000ml of a mixed solvent of water and acetonitrile (1:1), filtered, rinsed with a mixed solvent of water and acetonitrile (1:1), and the filter cake was dried under vacuum to give 305.4g, yield 81%, HPLC purity 98.6%.

The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, 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 process for the preparation of a compound of formula I, i.e. carbamatinib, comprising the steps of:

2. the method of claim 1, wherein the hydrolysis reaction of step (1) comprises reacting a compound of formula iii with 30% hydrogen peroxide under basic conditions in the presence of a catalyst to produce a compound of formula ii; preferably, the catalyst is selected from the group consisting of: tetramethylammonium chloride, tetraethylammonium chloride, tetrabutylammonium bromide, hexadecyltrimethylammonium bromide, benzyltriethylammonium chloride, or a combination of one, two or more thereof.

3. The method according to claim 1 or 2, wherein the weight/volume ratio g/ml of the compound of formula III to 30% hydrogen peroxide in the step (1) is 1 (10-50), such as 1 (15-40) or 1 (20-30).

4. The process according to any one of claims 1 to 3, wherein the hydrolysis reaction of step (1) is carried out in a first solvent immiscible with water; preferably, the first solvent is selected from: ethyl acetate, dichloromethane, dichloroethane, chloroform, toluene, xylene, or a combination of one, two or more thereof.

5. The process according to any one of claims 1 to 4, wherein the alkaline conditions of the hydrolysis reaction of step (1) are provided by the following reagents: sodium hydroxide, potassium hydroxide, lithium hydroxide, or a combination of one, two or three thereof.

6. The process according to any one of claims 1 to 5, wherein the methylation reaction of step (2) is carried out in a second solvent; preferably, the second solvent is selected from: n, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, acetone, acetonitrile, tetrahydrofuran, or a combination of one, two or more thereof.

7. The process according to any one of claims 1 to 6, wherein the methylation reaction of step (2) is carried out in the presence of a strongly basic reagent selected from the group consisting of: sodium hydroxide, sodium methoxide, sodium amide, sodium hydride, n-butyl lithium, lithium diisopropylamide, or a combination of one, two or more thereof.

8. The method according to any one of claims 1 to 7, wherein the methylating agent of step (2) is selected from: dimethyl sulfate, methyl iodide, dimethyl carbonate, monochloromethane and 1-methoxy-2, 2,6, 6-tetramethyl piperidine.

9. The process according to any one of claims 1 to 8, wherein the molar ratio of the compound of formula II to the methylating agent in step (2) is 1 (1-10), such as 1 (1-8), 1 (1-5) or 1 (1-3).

10. The process according to any one of claims 1 to 9, wherein the hydrolysis reaction of step (1) is carried out at a reaction temperature of 0 to 30 ℃, e.g. at room temperature, such as 20 to 25 ℃;

the reaction temperature of the methylation reaction of step (2) is 20 to 90 ℃, for example 30 to 80 ℃, 40 to 70 ℃, and exemplarily 60 ℃.