A process for the preparation of a zavegepant intermediate

Abstract

The application discloses a preparation method of a zavegepant intermediate. The method disclosed by the application takes compound I as a raw material, reacts with hippuric acid and an acylation reagent to obtain compound II, and then hydrolyzes and catalyzes with a transaminase to obtain a zavegepant intermediate compound VI. The method is simple in operation, high in production efficiency, and more suitable for industrial production.

Description

Technical fields:

[0001] This invention belongs to the field of medicinal chemistry, and specifically relates to a method for preparing a zavigepan intermediate. Background technology:

[0002] Zavegepant is a calcitonin gene-related peptide (CGRP) receptor antagonist and the first CGRP receptor antagonist nasal spray for the acute treatment of migraines in adults.

[0003] Compound VI is a key intermediate in the synthesis of zavigipan, as shown in Scheme 1.

[0004]

[0005] Scheme1

[0006] Organic Process Research & Development (2012), 16(12), 1953-1966. A method for synthesizing compound VI was reported. This method uses compound I as a starting material, which is condensed with hippuric acid to obtain compound III. Compound III is then hydrolyzed in two steps to obtain compound V, and finally, compound VI is obtained by transaminase catalysis, with an overall yield of 52.9%. This method uses a large amount of acetic anhydride as a solvent and requires alcoholysis and acidolysis to obtain compound V, as shown in Scheme 2.

[0007]

[0008] Scheme2

[0009] Therefore, we need to develop a new method for preparing zavigipan intermediates that is easy to operate, highly efficient, and suitable for industrial production. Summary of the Invention:

[0010] The purpose of this invention is to address the shortcomings of existing technologies by providing a method for preparing zavigipan intermediates.

[0011] On one hand, the present invention provides a method for preparing compound VI, comprising the following steps: using compound I as a raw material, reacting it with hippuric acid and an acylation reagent to obtain compound II, acid hydrolysis to obtain compound V, and finally catalyzing with transaminase to obtain compound VI. As shown in Scheme 3.

[0012]

[0013] R is selected from acetyl, propionyl, butyryl, isobutyryl, valeryl, with acetyl and propionyl being preferred.

[0014] Scheme3

[0015] Furthermore, the temperature of the acylation reaction is selected from 60 to 80°C, preferably 75 to 80°C.

[0016] Furthermore, the acylation reagent is selected from acetic anhydride, propionic anhydride, butyric anhydride, isobutyric anhydride, or valeric anhydride, with acetic anhydride and propionic anhydride being preferred.

[0017] Furthermore, the acylation reaction time is selected from 1 to 16 hours, preferably 16 hours.

[0018] On the other hand, the present invention provides a novel intermediate, a compound with the structure shown in Formula II, or a pharmaceutically acceptable salt thereof.

[0019]

[0020] The definition of R is as above.

[0021] The beneficial effects of this invention are that it discloses a method for preparing a zavigepan intermediate, comprising a novel compound II. Compared with reported compounds, compound II has lower solubility than compound III, making it easier to precipitate in the reaction solution and simplifying post-processing. Furthermore, this method only requires one acid hydrolysis step to obtain compound V. The method of this invention is simple to operate, has high production efficiency, low cost, and is suitable for industrial production. Attached image description:

[0022] Figure 1 Example 1: Proton NMR spectrum of compound IIa

[0023] Figure 2 Example 1: LCMS spectrum of compound IIa

[0024] Figure 3 Example 1: HPLC spectrum of compound IIa

[0025] Figure 4 Example 2: Proton NMR spectrum of compound IIb

[0026] Figure 5 Example 2: LCMS spectrum of compound IIb

[0027] Figure 6 Example 2: HPLC spectrum of compound IIb

[0028] Figure 7 Example 3: HPLC spectrum of compound V

[0029] Figure 8 Example 4: HPLC spectrum of compound V

[0030] Figure 9Example 5: HPLC spectrum of compound VI

[0031] Figure 10 Example 5: Chiral HPLC spectrum of compound VI Detailed implementation method:

[0032] The technical content of the present invention will be further described below with reference to specific embodiments, in order to better understand the content of the present invention, but the scope of protection of the present invention is not limited thereto.

[0033] Example 1: Preparation of compound IIa (R = acetyl group)

[0034]

[0035] Compound I (13.6 g), potassium acetate (11.7 g, 1.4 eq), hippuric acid (22.5 g, 1.5 eq), and toluene (136.0 mL, 10.0 v / w) were added to a 500 mL reaction flask. Acetic anhydride (27.2 mL, 2.0 v / w) was added, and the mixture was heated to 75–80 °C and reacted with mechanical stirring for 16 h. Samples were taken for analysis, and the reaction was found to be complete. The mixture was allowed to cool naturally to 15–20 °C, filtered, and washed twice with 2 V of toluene. The filter cake was transferred to a 250 mL beaker, 10 V of water was added, and the mixture was stirred at 15–20 °C for 30 min. The mixture was then filtered and washed twice with 2 V of water. The filter cake was dried in a forced-air oven at 50 °C to obtain 26.4 g of compound IIa, with a yield of 90.0% and an HPLC purity of 96.92%. 1 H-NMR such as Figure 1 As shown, LCMS is as follows Figure 2 As shown, HPLC Figure 3 As shown.

[0036] Example 2: Preparation of compound IIb (R = propionyl group)

[0037]

[0038] Compound I (10.0 g), potassium acetate (8.6 g, 1.4 eq), hippuric acid (16.8 g, 1.5 eq), and toluene (100.0 mL, 10.0 v / w) were added to a 500 mL reaction flask. Propionic anhydride (20.0 mL, 2.0 v / w) was added, and the mixture was heated to 75–80 °C and reacted with mechanical stirring for 16 h. Samples were taken for analysis, and the reaction was found to be complete. The mixture was allowed to cool naturally to 15–20 °C, filtered, and washed twice with 2 V toluene. The filter cake was transferred to a 250 mL beaker, 10 V water was added, and the mixture was stirred at 15–20 °C for 30 min. The mixture was then filtered and washed twice with 2 V water. The filter cake was dried in a forced-air oven at 50 °C to obtain 20.5 g of compound IIb, with a yield of 91.5% and an HPLC purity of 86.73%.1 H-NMR such as Figure 4 As shown, LCMS is as follows Figure 5 As shown, HPLC Figure 6 As shown.

[0039] Example 3 Preparation of compound V

[0040] 50% sulfuric acid (150.0 mL, 10.0 v / w) was added to a 500 mL reaction flask and mechanically stirred at 95–100 °C. Compound IIa (15.0 g) was added, and the reaction was stirred for 18 h. A sample was taken for analysis, and the reaction proceeded completely. 10 V of water was added to dilute to a 25% sulfuric acid aqueous solution. The temperature was gradually decreased (10 °C / 30 min) to 10 ± 2 °C. The mixture was filtered and washed with 2 V of water. The filter cake was transferred to a 250 mL reaction flask, and 3.5 V of methanol and 3.5 V of water were added. The mixture was mechanically stirred, heated to 60–65 °C, and reacted for 3 h. The temperature was then decreased to 15–20 °C, and the mixture was stirred for 2 h. The mixture was filtered and washed once with a mixture of water and methanol. The filter cake was dried at 50 °C with forced air to obtain 8.1 g of compound V, with a yield of 85.4% and an HPLC purity of 96.84%. Figure 7 As shown.

[0041] Example 4 Preparation of compound V

[0042] Add 150.0 mL of 50% sulfuric acid (10.0 v / w) to a 500 mL reaction flask, mechanically stir at 95–100 °C, add compound IIb (15.0 g), stir for 18 h, and sample for analysis; the starting material reaction was complete. Add 10 V of water to dilute to a 25% sulfuric acid aqueous solution, gradually cool (10 °C / 30 min) to 10 ± 2 °C, filter, and wash with 2 V of water. Transfer the filter cake to a 250 mL reaction flask, add 3.5 V of methanol and 3.5 V of water, mechanically stir, heat to 60–65 °C and react for 3 h, cool to 15–20 °C, stir for 2 h, filter, and wash once with a mixed solvent of water and methanol. Dry the filter cake at 50 °C with forced air to obtain 7.3 g of compound V, yield 80.0%, HPLC purity 98.42%. Figure 8 As shown.

[0043] Example 5: Preparation of Compound VI

[0044] 235.5 mL of purified water, 20.3 g of isopropylamine, and 15.0 g of compound V were added to a 1 L reaction flask. The pH of the system was adjusted to 8.0–8.5 with concentrated hydrochloric acid, and the system turned into a light brown clear liquid. Then, a prepared pyridoxal phosphate solution (7.5 mL, 2.0 g / L) and transaminase homogenate (Shanghai ES-ATA-156, 56.3 mL) were added sequentially to the system. The mixture was stirred at 32 °C for 48 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the filter cake was washed with 16.5 mL of water. The filter cake was dried under vacuum at 45 °C to obtain 13.6 g of off-white solid, with a yield of 90.0%, HPLC purity of 98.33%, and chiral purity of 99.22%. The HPLC analysis of compound VI is as follows: Figure 9 As shown, chiral HPLC Figure 10 As shown.

Claims

1. A method for preparing zavigepan intermediate VI, characterized in that, The method uses compound I as a raw material, which undergoes an acylation reaction to obtain compound II, followed by hydrolysis and transaminase catalysis to obtain compound VI. The preparation method is shown below. R is selected from acetyl, propionyl, butyryl, isobutyryl, and valeryl.

2. The preparation method according to claim 1, characterized in that, The temperature of the acylation reaction is selected from 60 to 80 °C.

3. The preparation method according to claim 1, characterized in that, The reagents used in the acylation reaction are selected from acetic anhydride, propionic anhydride, butyric anhydride, isobutyric anhydride, or valeric anhydride.

4. The preparation method according to claim 1, characterized in that, The acylation reaction time is selected from 1 to 16 hours.

5. A compound represented by Formula II, or a pharmaceutically acceptable salt thereof, in, The definition of R is as above.

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