CN113024459A - Alvatinib mesylate intermediate impurity and preparation method thereof - Google Patents

Abstract

The invention discloses a varlitinib mesylate intermediate impurity and a preparation method thereof. The preparation method of the impurity compound comprises the step of heating and reacting 4-amino-3-chlorophenol hydrochloride with 4-chloro-5-methoxyquinoline-8-carboxamide.

Description

Alvatinib mesylate intermediate impurity and preparation method thereof

Technical Field

The invention belongs to the technical field of pharmaceutical chemistry, and relates to relative impurities of varlitinib mesylate and a preparation process thereof.

Background

The related statistical data show that the primary hepatocellular carcinoma is one of the common malignant tumors in the world, while China is a high-incidence country of the hepatocellular carcinoma, the morbidity and the mortality are respectively ranked in the third place and the second place in the malignant tumors, about 46.6 ten thousand people are attacked and 42.2 ten thousand people are killed each year, and the number of the attacked and dead people exceeds 50 percent of the whole world, thereby seriously threatening the physical health of people in China.

On day 17/8 in 2018, after the FDA approved the use of lenvatinib mesylate (lenviima), independently developed by wakame japan corporation, for first-line treatment of unresectable hepatocellular carcinoma (HCC), on day 4/9, the national drug administration also approved that lenvatinib mesylate was marketed in china and used for the same indications. Varenib mesylate (lenviima) is a multi-target drug that is an oral multi-RTK inhibitor that, in addition to inhibiting other angiogenesis and oncogenic signaling pathway related RTKs involved in tumor proliferation, including the receptors PDGFR, KIT and RET of platelet derived growth factor PDGF, is also capable of selectively inhibiting the kinase activity of Vascular Endothelial Growth Factor (VEGF) receptors (VEGFR 1, VEGFR2, VEGFR 3) and Fibroblast Growth Factor (FGF) receptors (FGFR1, FGFR2, FGFR 3).

According to the synthesis process of the first-step intermediate of the varlitinib mesylate, related impurities of the intermediate of the varlitinib mesylate can be generated through the following routes:

。

the target impurities are discovered and directionally synthesized, an analysis method of the target impurities is established, and the method has important significance for effectively controlling the quality of the raw material medicine of the varlitinib mesylate.

Disclosure of Invention

The invention provides an impurity B compound generated in the synthesis of an intermediate 4- (4-amino-3-chlorophenoxy) -7-methoxyquinoline-6-carboxamide of varlitinib mesylate and a preparation method of the impurity B compound. Since 4- (4-amino-3-chlorophenoxy) -7-methoxyquinoline-6-carboxamide is a key intermediate for preparing the ranvatinib mesylate, the quality control of the intermediate is very important for the quality control of the subsequent final product (the ranvatinib mesylate), and the impurity B compound has a genotoxicity warning structure, the monitoring of the impurity B compound is very important for improving and ensuring the quality of the ranvatinib mesylate.

In one embodiment of the invention, the invention provides a varlitinib mesylate intermediate impurity B, i.e., a compound of formula I, having the following chemical structural formula:

。

in another embodiment, the present invention provides a process for the preparation of the impurity B of varenib mesylate, a compound of formula I, comprising the steps of,

a) dissolving 4-amino-3-chlorophenol hydrochloride in a polar aprotic solvent, stirring for reaction in the presence of an inorganic strong base, and adding 4-chloro-5-methoxyquinoline-8-carboxamide for heating reaction;

b) after the reaction is finished, the mixed solution of the organic solvent is dripped into the solution, the natural cooling is started after the dripping is finished, and the ice-water bath cooling crystallization is started after the temperature is reduced to the room temperature. And after crystallization, starting suction filtration, washing a filter cake by using an organic solvent, and drying under reduced pressure to obtain an impurity B compound.

The further technical scheme is as follows: the polar aprotic solvent of step a) is dimethyl sulfoxide; the inorganic strong base is a potassium hydroxide solution with the mass fraction of 40-50%, and the dosage of the potassium hydroxide is 2.5-3.5eq of 4-chloro-5-methoxyquinoline-8-carboxamide; the heating reaction temperature is 60-80 ℃, and the heating reaction time is 12-21 h.

In the step b), the organic solvent dropped into the reaction solution is mixed solution of acetone and purified water in a volume ratio of 1:2, the organic solvent used for washing is acetone, and the washing is carried out for 2 to 3 times; the room temperature is 20-30 ℃, and the temperature is reduced to 0-10 ℃ in an ice water bath.

The invention also aims to provide a bulk drug containing the pharmaceutical drug containing the methanesulfonic acid lunatinib and the compound shown in the formula I, wherein the content of the compound shown in the formula I or the salt thereof relative to the methanesulfonic acid lunatinib is lower than 60ppm, preferably lower than 10ppm or lower.

The invention also relates to the use of a compound of formula I or a salt thereof as a standard or control.

The beneficial results of the invention are:

the impurity B compound (compound shown in the formula I) of the key intermediate of the varlitinib mesylate and the preparation method thereof are prepared for the first time, the purity of the impurity B of the varlitinib mesylate prepared by the method is more than 98%, and the impurity B can be used for quality research and production quality control of the varlitinib mesylate. Therefore, the compound can be used as a standard substance and a reference substance for controlling the quality of the intermediate 4- (4-amino-3-chlorophenoxy) -7-methoxyquinoline-6-carboxamide and the quality of the methanesulfonic acid lunvatinib, and ensuring the quality of the key intermediate so as to ensure the quality of the final methanesulfonic acid lunvatinib product.

Drawings

FIG. 1 shows an HPLC chromatogram of the impurity B of varlitinib mesylate.

FIG. 2 shows the mass spectrum of the impurity B of varlitinib mesylate.

FIG. 3 shows the hydrogen spectrum of impurity B of varlitinib mesylate.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

Example 1 preparation of Lunvatinib mesylate impurity B

4-amino-3-chlorophenylate (9.89 g, 54.85 mmol) and 90 mL of DMSO were placed in a 250 mL three-necked flask, and the mixture was stirred at room temperature for 20 to 30 min to completely dissolve the solid. Slowly dripping 40% potassium hydroxide solution, and stirring and reacting for 15-25 min after finishing the dripping. 4-chloro-5-methoxyquinoline-8-carboxamide (10 g, 42.26 mmol) was added to the reaction mixture, the temperature was raised to 60-70 ℃ and the reaction was allowed to incubate for 15 h. After completion of the reaction, a mixed solvent of 50mL of acetone and 100mL of purified water was added dropwise to the reaction mixture. After the dropwise addition, the temperature is naturally reduced, and then the temperature is reduced and crystallization is carried out by using an ice water bath. After crystallization, the mixture is filtered, and dried under reduced pressure to obtain 13.5 g of impurity B, wherein the yield is 93.00 percent, and the purity is 98.73 percent.

HPLC purity chromatographic conditions were as follows:

the instrument comprises the following steps: high performance liquid chromatograph

A chromatographic column: YMC-Pack Pro C184.6 with 150mm 5 μm

Sample introduction amount: 20 mu l

Flow rate: 1ml/min

Detection wavelength: 265nm

Column temperature: 25 deg.C

Mobile phase: gradient elution was performed using methanol-water (50: 950) as mobile phase A and acetonitrile-methanol-water (700: 200: 100) as mobile phase B according to the following table

Time (min)	A（%）	B（%）
			0	85	15
5	85	15
			35	55	45
45	10	90
			50	10	90
50.01	85	15
			60	85	15

The purity of the obtained sample was 98.73% by checking according to the above conditions, and the content value was 98.36% by calculation after the loss on drying and the residue were measured.

And (5) detecting by hydrogen spectrum mass spectrum, and confirming the structure to be consistent with the structure of the target molecule.

MS (m/z): 344[ M + H ] +. See FIG. 2

1H NMR (600 MHz, DMSO-d6) delta 10.36 (d, J = 4.5 Hz, 1H), 8.70 (d, J = 5.3 Hz, 1H), 8.60 (d, J = 8.6 Hz, 1H), 7.67 (d, J = 4.5 Hz, 1H), 7.20 (d, J = 8.7 Hz, 1H), 7.16 (d, J = 2.5 Hz, 1H), 6.97-6.89 (m, 2H), 6.66 (d, J = 5.3 Hz, 1H), 5.43 (s, 2H), 3.97 (s, 3H); see FIG. 3.

The impurities are detected by adopting a high performance liquid chromatography, and the detection method comprises the following steps:

1. chromatographic conditions are as follows:

the instrument comprises the following steps: high performance liquid chromatograph

A chromatographic column: YMC-Pack Pro C184.6 mm, 5 μm

Sample introduction amount: 20 mu l

Flow rate: 1ml/min

Detection wavelength: 265nm

Column temperature: 40 deg.C

Mobile phase: gradient elution was performed using methanol-water (50: 950) as mobile phase A and acetonitrile-methanol-water (700: 200: 100) as mobile phase B according to the following table

Time (min)	A（%）	B（%）
			0	90	10
35	55	45
			45	10	90
50	10	90
			50.01	90	10
60	90	10

2. The determination method comprises the following steps:

control solution: taking 10mg of impurity B, precisely weighing, placing in a 100ml measuring flask, dissolving with methanol, diluting to scale, and shaking up to obtain impurity stock solution; precisely measuring 1ml of each impurity stock solution, putting the impurity stock solution into a 20ml measuring flask, diluting the impurity stock solution to a scale with a diluent, and shaking up to obtain an impurity mixed solution; precisely measuring 1ml of impurity mixed solution, placing the impurity mixed solution into a 100ml measuring flask, diluting the impurity mixed solution to a scale with a diluent, and shaking up to obtain an impurity reference solution.

Test solution: weighing about 25mg of a sample to be tested, precisely weighing, placing in a 50ml measuring flask, adding about 30ml of diluent, ultrasonically dissolving, diluting with the diluent to scale, shaking up, precisely weighing 5ml, placing in a 25ml measuring flask, diluting with the diluent to scale, and shaking up.

And precisely measuring 20 mul of the solution, respectively injecting the solution into a liquid chromatograph, and recording a chromatogram.

3. Formula for calculation

Calculated by peak area external standard method

Impurity content (%) =

In the formula, C_{To pair}-control content;

A_{to pair}-peak area of control solution;

A-peak area of the test solution;

V-the dilution volume of the test solution, ml;

V _{to pair}-dilution volume of control solution, ml;

m-sample weighing of reference substance, mg;

m-sample weight of the sample, mg.

Three batches of intermediate 4- (4-amino-3-chlorophenoxy) -7-methoxyquinoline-6-carboxamide were tested as described above, with impurity B contents of 80ppm, 60ppm and 45 ppm respectively. And detecting the corresponding three batches of final product varlitinib mesylate, wherein the contents of the impurity B are respectively 10ppm, 6ppm and 0ppm (lower than detection limit).

Finally, the above embodiments are only used to illustrate the spirit of the technical solution of the present invention and are not limited. While the present invention has been described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.

Claims (9)

1. A compound of formula I and possible salts thereof,

。

2. a process for preparing a compound of formula I, comprising the steps of:

，

a) dissolving 4-amino-3-chlorophenol hydrochloride in a polar aprotic solvent, stirring for reaction in the presence of an inorganic strong base, and adding 4-chloro-5-methoxyquinoline-8-carboxamide for heating reaction;

b) after the reaction is finished, dropwise adding the mixed solution of the organic solvent into the solution, cooling after the dropwise adding is finished, cooling to room temperature, cooling in an ice water bath for crystallization, filtering after the crystallization is finished, washing a filter cake with the organic solvent, and drying under reduced pressure to obtain the compound of the formula I.

3. The method of claim 2, wherein the polar aprotic solvent is dimethyl sulfoxide.

4. The method of claim 2, wherein the inorganic strong base is a potassium hydroxide solution with a mass fraction of 40% to 50%, and the amount of the potassium hydroxide is 2.5 to 3.5eq of 4-chloro-5-methoxyquinoline-8-carboxamide.

5. The method of claim 2, wherein the heating reaction temperature is 60-80 ℃, and the heating reaction time is 12-21 h.

6. The method according to claim 2, wherein the organic solvent added dropwise to the reaction solution in step b) is a mixture of acetone and purified water at a volume ratio of 1:2, and the organic solvent used for washing is acetone, and the washing is performed 2 to 3 times.

7. The method of claim 2, wherein the room temperature in step b) is 20-30 ℃, and the temperature of the ice water bath is reduced to 0-10 ℃.

8. Use of a compound of formula I according to claim 1 or a salt thereof as a control or standard.

9. A raw material drug of varlitinib mesylate, wherein the content of a compound shown in a formula I or a salt thereof is not more than 60 ppm.

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