Preparation method of high-optical-purity litamilast

Abstract

The invention belongs to the technical field of medicine preparation, and particularly relates to a preparation method of high-optical-purity litamilast. According to the method, an acetonitrile aqueous solution with a specific concentration is taken as a solvent, a litamilast crude product and (S)-(-)-N-benzyl-1-phenyl-ethylamine are salified, and litamilast (S)-(-)-N-benzyl-1-phenyl-ethylamine salt is separated out by utilizing the solubility difference of the salified isomer in the solvent, so that the litamilast (S)-(-)-N-benzyl-1-phenyl-ethylamine salt is obtained. (S)-(-)-N-benzyl-1-phenyl-ethylamine salt of an isomer impurity A of the compound is dissolved in a solvent. And dissociating by using (S)-(-)-N-benzyl-1-phenyl-ethylamine hydrochloride of the litamilast hydrochloride, so as to obtain the litamilast with high optical purity. The method is simple in technological process, high-optical-purity litamilast can be obtained through one-time preparation, operation is easy, the solvent can be recycled, cost is low, and the method is environmentally friendly and suitable for large-scale industrial production and has excellent industrial application prospects.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparation, and particularly relates to a preparation method of lifitegrast with high optical purity. Background Art

[0002] Lifitegrast was developed by Shire Pharmaceuticals and is the first prescription drug approved to treat the signs and symptoms of dry eye by inhibiting the inflammation caused by dry eye. Lifitegrast can inhibit the binding of LFA-1 to ICAM-1, thereby reducing the level of inflammation mediated by T lymphocytes. It can not only treat the eye damage caused by dry eye, but also relieve the discomfort symptoms. Its structure is shown as follows:

[0003] The preparation methods of lifitegrast include the ester hydrolysis or hydrogenation reaction of its precursors. As shown in Route 1, WO2009139817A2, WO2011050175A1 and WO2019096996A1 disclose that the compound of formula II is hydrogenated to obtain lifitegrast under the catalysis of noble metal palladium carbon. However, this route has noble metal residues and high production costs.

[0004]

[0005] As shown in Route 2, CN104797574A1 can obtain lifitegrast by the base hydrolysis of the compound of formula III. This process seems simple, but in actual production, the chiral configuration of chiral amino acid derivatives is prone to racemization under strong alkaline conditions, generating impurity A, which is very unfavorable for the purification of lifitegrast.

[0006]

[0007] The above-mentioned literatures all use the method of debenzylation of formula II to prepare lifitegrast. Through the experimental demonstration of the inventor, in the actual reaction process, the above methods all have the problem that the chiral configuration is prone to racemization, generating the enantiomeric impurity A of lifitegrast, resulting in the chiral purity of lifitegrast being less than 99.8%, which further affects the clinical efficacy of lifitegrast and increases the drug safety risk.

[0008] In view of this, developing a preparation method to improve the optical purity of lifitegrast has important research value for optimizing the drug synthesis process of lifitegrast and improving drug safety. Summary of the Invention

[0009] The object of the present invention is to solve the problems existing in the above-mentioned prior art, and provides a preparation method of ritlecitinib with high optical purity, which has simple process operation, recyclable solvent, low cost and is environmentally friendly. This method uses a specific mixed solution of water and acetonitrile as the solvent, and high optical purity ritlecitinib can be obtained by one-time preparation.

[0010] To achieve the above object, the technical solution adopted by the present invention is as follows: The present invention provides a preparation method of ritlecitinib with high optical purity, comprising the following steps: 1) Salifying ritlecitinib containing isomers, namely ritlecitinib crude product, with (S)-(-)-N-benzyl-1-phenylethylamine in a solvent to obtain ritlecitinib (S)-(-)-N-benzyl-1-phenylethylamine salt; 2) Dissociating the ritlecitinib (S)-(-)-N-benzyl-1-phenylethylamine salt prepared in step 1) with an acid in a solvent to obtain ritlecitinib.

[0011] As an embodiment of the present invention, the solvent in step 1) of the above preparation method is selected from a mixed solution of water and acetonitrile, preferably an aqueous acetonitrile solution with a mass fraction percentage of 85% - 95%. The inventors studied the influence of acetonitrile aqueous solutions with different mass percentage concentrations on the purification results (all dissolved clearly with 20 times the solvent), and the results are shown in Table 1. Table 1 Influence of acetonitrile aqueous solutions with different mass percentage concentrations on the purification results

[0012] The results show that when the mass percentage concentration of the acetonitrile aqueous solution is 80 - 95%, the precipitated solid has good properties and the quality is controllable.

[0013] As an embodiment of the present invention, the mass percentage content of impurity A in the ritlecitinib crude product is 0.5% - 2%.

[0014] As an embodiment of the present invention, the molar ratio of the ritlecitinib crude product to (S)-(-)-N-benzyl-1-phenylethylamine is 1:(0.9 - 1.1); and / or, the mass ratio of the ritlecitinib crude product to the solvent is 1:(10 - 20). The inventors studied the influence of different molar ratios of the ritlecitinib crude product to (S)-(-)-N-benzyl-1-phenylethylamine on the result of step 1) of the present application (Table 2): Table 2 Screening of the molar ratio of ritlecitinib crude product to (S)-(-)-N-benzyl-1-phenylethylamine

[0015] The results show that when the molar ratio of the crude loteprednol etabonate to (S)-(-)-N-benzyl-1-phenylethylamine is 1:(0.9 - 1.1), the precipitated solid has good properties and the quality is controllable.

[0016] In addition, the inventors studied the effect of the mass ratio of the crude loteprednol etabonate to the solvent (an aqueous acetonitrile solution with a mass percentage concentration of 90%) on the purification result, and the results are shown in Table 3: Table 3 Effect of the mass ratio of the crude loteprednol etabonate to the solvent on the purification result

[0017] The results show that when the mass ratio of the crude loteprednol etabonate to the solvent is 1:(10 - 20), the precipitated solid has good properties and the quality is controllable.

[0018] As an embodiment of the present invention, the reaction temperature in step 1) is 40 - 50 °C.

[0019] As an embodiment of the present invention, the solvent in step 2) is a mixed solution of alcohol and water. When the (S)-(-)-N-benzyl-1-phenylethylamine salt of loteprednol etabonate is dissociated with an acid in the alcohol-water mixture, the mass ratio of the (S)-(-)-N-benzyl-1-phenylethylamine salt of loteprednol etabonate to the mixed solution of alcohol and water is 1:(10 - 20); the inventors studied the effect of the mass ratio of the (S)-(-)-N-benzyl-1-phenylethylamine salt of loteprednol etabonate to the alcohol-water (a methanol aqueous solution with a mass fraction of 20%) on the product (Table 4): Table 4 Screening of the mass ratio of the (S)-(-)-N-benzyl-1-phenylethylamine salt of loteprednol etabonate to the alcohol-water

[0020] The results show that when the mass ratio of the (S)-(-)-N-benzyl-1-phenylethylamine salt of loteprednol etabonate to the alcohol-water (a methanol aqueous solution with a mass fraction of 20%) is 1:(10 - 20), the precipitation situation is better and the quality and yield are stable.

[0021] As an embodiment of the present invention, in the mixed solvent of alcohol and water in step 2), the alcohol is selected from one or more of methanol, ethanol, and isopropanol, and methanol is preferred.

[0022] As an embodiment of the present invention, the mixed solvent of alcohol and water in step 2) is selected from a 10% - 20% methanol aqueous solution, and a 20% methanol aqueous solution is preferred.

[0023] As an embodiment of the present invention, the acid in step 2) is selected from one or more of hydrochloric acid, sulfuric acid, and acetic acid, and hydrochloric acid is preferred, and the pH value is adjusted to 2 - 6 with the acid.

[0024] The beneficial effects of the present invention are as follows: The present invention provides a method for preparing ritlecitinib with high optical purity. Using an acetonitrile aqueous solution with a specific concentration as a solvent, the crude ritlecitinib and (S)-(-)-N-benzyl-1-phenylethylamine are salted out. By utilizing the difference in solubility of their isomers in the solvent, the (S)-(-)-N-benzyl-1-phenylethylamine salt of ritlecitinib is separated, while the (S)-(-)-N-benzyl-1-phenylethylamine salt of its isomer impurity A dissolves in the solvent. Then, the (S)-(-)-N-benzyl-1-phenylethylamine salt of ritlecitinib is dissociated with hydrochloric acid to obtain ritlecitinib with high optical purity. The method of the present invention has a simple technological process, can obtain ritlecitinib with high optical purity in one preparation, is easy to operate, the solvent can be recycled and reused, has low cost, is environmentally friendly, is suitable for large-scale industrial production, and has excellent industrial application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 is the HPLC chromatogram of crude ritlecitinib, CP-G-A is the isomer of ritlecitinib, and CP is ritlecitinib.

[0026] Figure 2 is the HPLC chromatogram of ritlecitinib in Example 1, CP-G-A is the isomer impurity A of ritlecitinib, and CP is ritlecitinib.

[0027] Figure 3 is the HPLC chromatogram of ritlecitinib in Example 2, CP-G-A is the isomer impurity A of ritlecitinib, and CP is ritlecitinib.

[0028] Figure 4 is the HPLC chromatogram of ritlecitinib in Example 3, CP-G-A is the isomer impurity A of ritlecitinib, and CP is ritlecitinib. EMBODIMENTS

[0029] To make the objectives, technical solutions and advantages of the present invention clearer, the following examples are provided to further elaborate on the present invention in detail. The specific examples described herein are only for explaining the present invention and do not constitute any limitation to the present invention. In addition, in the following description, the description of well-known technologies is omitted to avoid unnecessary conceptual confusion. Such technologies are also described in many publications.

[0030] DEFINITIONS Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as commonly used in the field described in the present invention. EXAMPLE 1

[0031] This example provides a method for preparing ritlecitinib with high optical purity, including the following steps: 30 g (0.049 mol) of ritlecitinib crude product (optical purity 98.98%, such as Figure 1 ), and 10.8 g (0.051 mol, 1.04 eq) of (S)-(-)-N-benzyl-1-phenylethylamine were added to a 1000 mL single-necked flask. 450 g of an aqueous acetonitrile solution with a mass percentage concentration of 95% was added, and the temperature was raised to 50 °C until it was completely dissolved. Then the temperature was lowered to 10 °C for crystallization. After a large amount of solid precipitated, crystallization was continued for 2 h and then filtered to obtain a wet product of ritlecitinib (S)-(-)-N-benzyl-1-phenylethylamine salt; 40 g of the wet product of ritlecitinib (S)-(-)-N-benzyl-1-phenylethylamine salt was added to 800 g of an aqueous ethanol solution with a mass percentage concentration of 20%. It was stirred until completely dissolved, and then hydrochloric acid was slowly added dropwise to adjust the pH value to 5 - 6. A large amount of solid precipitated, and it was filtered and dried to obtain 24 g of ritlecitinib.

[0032] After detection, the chiral purity of the obtained ritlecitinib was 99.16%, such as Figure 2 . Example 2

[0033] This example provides a method for preparing ritlecitinib with high optical purity, including the following steps: 60 g (0.097 mol) of ritlecitinib crude product (optical purity 98.98%, such as Figure 1 ), and 21.6 g (0.102 mol, 1.05 eq) of (S)-(-)-N-benzyl-1-phenylethylamine were added to a 2000 mL single-necked flask. 1200 g of an aqueous acetonitrile solution with a mass percentage concentration of 85% was added, and the temperature was raised to 50 °C until it was completely dissolved. Then the temperature was lowered to 10 °C for crystallization. After a large amount of solid precipitated, crystallization was continued for 2 h and then filtered to obtain a wet product of ritlecitinib (S)-(-)-N-benzyl-1-phenylethylamine salt; 85 g of the wet product of ritlecitinib (S)-(-)-N-benzyl-1-phenylethylamine salt was added to 800 g of an aqueous methanol solution with a mass percentage concentration of 20%. It was stirred until completely dissolved, and then hydrochloric acid was slowly added dropwise to adjust the pH value to 2 - 3. A large amount of solid precipitated, and it was filtered and dried to obtain 50 g of ritlecitinib.

[0034] After detection, the chiral purity of the obtained ritlecitinib was 99.94%, such as Figure 3 . Example 3

[0035] This example provides a method for preparing ritlecitinib with high optical purity, including the following steps: 40 g (0.065 mol) of ritlecitinib crude product (optical purity 98.98%, such as Figure 140 g (0.065 mol) of crude ralitazone (optical purity 98.98%, as 45 g of the wet product of ralitazone (S)-(-)-N-benzyl-1-phenylethylamine salt was added to 900 g of a 10% methanol-water solution by mass. It could not be dissolved clearly at room temperature and could only be dissolved clearly by stirring at 50 °C (the product was prone to other degradation impurities at too high temperatures). Then hydrochloric acid was slowly added dropwise to adjust the pH value to 2-3. A large amount of solid precipitated out. After filtration and drying, 35 g of ralitazone was obtained.

[0036] After detection, the chiral purity of the obtained ralitazone was 99.94%, as Figure 4 . Example 4

[0037] This example provides a method for preparing ralitazone with high optical purity, including the following steps: 40 g (0.065 mol) of crude ralitazone (optical purity 98.98%, as Figure 1 ), and 14.4 g (0.068 mol, 1.05 eq) of (S)-(-)-N-benzyl-1-phenylethylamine were added to a 1000 mL single-necked flask. 720 g of an aqueous acetonitrile solution with a mass percentage concentration of 80% was added. The temperature was raised to 50 °C to dissolve it clearly, and then cooled to 10 °C for crystallization. After a large amount of oil-like substances precipitated out, crystallization was continued for 2 h, but the precipitate was still a white oil-like substance, and it was impossible to obtain a wet product of ralitazone (S)-(-)-N-benzyl-1-phenylethylamine salt with good properties. Example 5

[0038] This example provides a method for preparing ralitazone with high optical purity, including the following steps: 40 g (0.065 mol) of crude ralitazone (optical purity 98.98%, as Figure 1 ), and 14.4 g (0.068 mol, 1.05 eq) of (S)-(-)-N-benzyl-1-phenylethylamine were added to a 1000 mL single-necked flask. 720 g of acetonitrile was added. The temperature was raised to 50 °C to dissolve it clearly, and then cooled to 10 °C for crystallization. No solid precipitated out. Crystallization was continued for 24 h, but still no solid precipitated out, and it was impossible to obtain a wet product of ralitazone (S)-(-)-N-benzyl-1-phenylethylamine salt.

Claims

1. A method for preparing ritlecitinib with high optical purity, characterized in that, the method comprises: 1) Salifying ritlecitinib containing isomers, namely ritlecitinib crude product, with (S)-(-)-N-benzyl-1-phenylethylamine in a solvent to obtain ritlecitinib (S)-(-)-N-benzyl-1-phenylethylamine salt; 2) Dissociating the ritlecitinib (S)-(-)-N-benzyl-1-phenylethylamine salt prepared in step 1) with an acid in a solvent to obtain ritlecitinib.

2. The method for preparing ritlecitinib with high optical purity according to claim 1, characterized in that, the solvent in step 1) is a mixed solution of water and acetonitrile.

3. The method for preparing ritlecitinib with high optical purity according to claim 1, characterized in that, the solvent in step 1) is selected from an aqueous acetonitrile solution with a mass fraction percentage of 85% - 95%.

4. The method for preparing ritlecitinib with high optical purity according to claim 1, characterized in that, the molar ratio of the ritlecitinib crude product to (S)-(-)-N-benzyl-1-phenylethylamine in step 1) is 1:(0.9 - 1.1).

5. The method for preparing ritlecitinib with high optical purity according to any one of claims 1 - 4, characterized in that, the mass ratio of the ritlecitinib crude product to the solvent in step 1) is 1:(10 - 20).

6. The method for preparing ritlecitinib with high optical purity according to claim 1, characterized in that, the reaction temperature in step 1) is 40 - 50 °C.

7. The method for preparing ritlecitinib with high optical purity according to claim 1, characterized in that, the solvent in step 2) is a mixed solution of alcohol and water, and the mass ratio of ritlecitinib (S)-(-)-N-benzyl-1-phenylethylamine salt to alcohol and water is 1:(10 - 20).

8. The method for preparing ritlecitinib with high optical purity according to claim 7, characterized in that, the alcohol is selected from one or more of methanol, ethanol, and isopropanol, preferably methanol.

9. The method for preparing ritlecitinib with high optical purity according to claim 8, characterized in that, the solvent is a 10% - 20% aqueous methanol solution, preferably a 20% aqueous methanol solution.

10. The method for preparing ritlecitinib with high optical purity according to claim 1, characterized in that, the acid in step 2) is selected from one or more of hydrochloric acid, sulfuric acid, and acetic acid, preferably hydrochloric acid, and the pH value is adjusted to 2 - 6 with the acid.

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