A process for the preparation of a CGRP receptor antagonist intermediate

Abstract

The application discloses a method for preparing a CGRP receptor antagonistic intermediate, and belongs to the field of synthesis of medical intermediates. Compound 1 is used as a raw material, reacts with hydroxylamine hydrochloride in an organic solvent to generate an intermediate 2, and then reacts in the presence of a reducing agent to obtain a remikiren intermediate 3. The application is characterized in that a large steric hindrance silicon group is used as the R substituent in the compound 1, so that high stereoselectivity is ensured in the reduction reaction. The key intermediate obtained by using the method has high chiral purity, and the operation is simple, so that the industrial production of the product in the later stage can be realized.

Description

Technical Field

[0001] This invention relates to a method for preparing intermediates of CGRP receptor antagonists, belonging to the field of pharmaceutical intermediate synthesis. Background Technology

[0002] Rimegepant, developed by Biohaven Pharmaceuticals, is an oral CGRP receptor antagonist used for the acute treatment of migraines in adults. As a CGRP-targeting drug, rimegepant inhibits acute migraine attacks by blocking the binding of CGRP to its receptors, reducing the activity of the trigeminal vascular system. It was the first CGRP-targeting drug to demonstrate efficacy in both acute and preventative treatment of migraines. It was approved for marketing by the U.S. Food and Drug Administration (FDA) on February 27, 2020.

[0003] In the synthesis process of Remdesivir, intermediate 3 is a key intermediate, and the other chiral center configuration of the drug molecule is mainly formed in these two steps. Currently, there are two main methods for synthesizing intermediate 3:

[0004] A. Transaminase-catalyzed method: This method involves the asymmetric synthesis of intermediate 3, an amination product, using transaminase under ammonia source conditions. Enzyme-catalyzed asymmetric preparation offers significant advantages such as high conversion rates, good stereoselectivity, mild reaction conditions, and environmental friendliness. However, this method suffers from difficulties in enzyme acquisition, preservation of enzyme activity and catalytic capacity, and the fact that most enzyme-catalyzed reactions are single-use, making reuse difficult and resulting in high costs. Furthermore, it requires sophisticated equipment and involves cumbersome operation.

[0005] B. Amination-reduction method: This method involves amination of isopropyl titanate under ammonia pressure of 100 Psi, followed by hydrogenation reduction using Pd / Al2O3 catalysis under ammonia pressure of 100 Psi to obtain product intermediate 3. The amination-reduction method for both amination and asymmetric hydrogenation requires ammonia, which causes significant environmental pollution and necessitates stringent personnel safety measures. Furthermore, the hydrogenation method has low safety profiles, making it unsuitable for large-scale preparation and industrial production.

[0006] Therefore, there is an urgent need in this field to develop a method for preparing key intermediates of retinoic acid that is low-cost, easy to operate, has a high yield, and is suitable for industrial production. Summary of the Invention

[0007] To overcome the aforementioned technical deficiencies, this invention provides a method for synthesizing a key intermediate of rememegapan, thereby addressing the shortcomings of existing methods described in the background section. The core technical solution involves using compound 1 as a raw material, reacting it with hydroxylamine hydrochloride in an organic solvent to generate intermediate 2, followed by a reaction in the presence of a reducing agent to obtain rememegapan intermediate 3; subsequently, it reacts with hydrochloric acid or hydrogen chloride to generate rememegapan intermediate 3 hydrochloride.

[0008] The method for preparing rimex intermediate 3 according to the present invention is represented by the following reaction equation:

[0009]

[0010] Where R is a silicon protection base with high steric resistance.

[0011] The present invention discloses a method for preparing a rememegapan intermediate, comprising the following steps: using compound 1 as a raw material, reacting it with hydroxylamine hydrochloride in an organic solvent to generate intermediate 2, and then reacting it in the presence of a reducing agent to obtain rememegapan intermediate 3.

[0012] Furthermore, in the above technical solution, the high steric retardation silicon protection substrate is selected from TBS or TIPS.

[0013] Furthermore, in the above technical solution, the organic solvent is selected from methanol, ethanol, or isopropanol.

[0014] Furthermore, in the above technical solution, the molar ratio of compound 1 to hydroxylamine hydrochloride is 1:1-8.

[0015] Furthermore, in the above technical solution, in the first step, an organic base is added to the reaction; the organic base is selected from pyridine or DMAP.

[0016] Furthermore, in the above technical solution, the reducing agent is selected from zinc powder, Raney nickel, or palladium on carbon.

[0017] Furthermore, in the above technical solution, the zinc powder and acid form a reduction system; Raney nickel or palladium on carbon needs to be pressurized to 60-150 psi in the presence of hydrogen to react.

[0018] Furthermore, in the above technical solution, after the reduction reaction is completed, hydrochloric acid or hydrogen chloride solution is added to generate Remegapan intermediate 3 hydrochloride.

[0019] Beneficial effects of the invention

[0020] The key to this invention lies in the use of a sterically hindered silicon group as the R substituent in compound 1, ensuring high specificity and stereoselectivity during the reduction reaction. The key intermediate obtained using the method of this invention exhibits high chiral purity, is easy to operate, and can facilitate the industrial-scale production of this product in later stages. Detailed Implementation

[0021] Example 1: Synthesis of Intermediate 2

[0022]

[0023] 44.6 g (0.1 mol) of intermediate 1a, 34.7 g (0.5 mol) of hydroxylamine hydrochloride, and 446 mL of ethanol were mixed, purged with nitrogen, and refluxed for 24 h. The mixture was concentrated to dryness, 100 mL of water was added, and the mixture was extracted with ethyl acetate, dried, and concentrated to dryness. Heptane was added to crystallize the mixture, and the crystals were filtered and dried to give 29 g of compound 2a, a white solid, with a yield of 63%.

[0024] Example 2: Synthesis of Intermediate 2

[0025] 44.6 g (0.1 mol) of intermediate 1a, 34.7 g (0.5 mol) of hydroxylamine hydrochloride, and 446 mL of ethanol were mixed. The pH of the reaction system was adjusted to 4-5 using DMAP, and the mixture was purged with nitrogen and refluxed for 24 h. The mixture was concentrated to dryness, and 100 mL of water was added. The mixture was extracted with ethyl acetate, dried, and concentrated to dryness. Heptane was added to induce crystallization, and the crystals were filtered and dried to give 33.6 g of compound 2a as a white solid, with a yield of 72%. MS(ESI)[M+H] + =461.2; 1 H NMR (400MHz, CDCl3) δ8.42(dd,J=5.0,1.6Hz,1H),8.27(s,1H),7.69(d,J=7.4Hz,1H),7.31–7.16(m,1H),7.00–6.83(m,2H),6.83– 6.73(m,1H),5.08(dd,J=4.6,1.7Hz,1H),4.60(dd,J=12.6,2.6Hz,1H),2.19–1.97(m,2H),1.81–1.47(m,2H),1.09–0.74(m,21H).

[0026] Example 3: Synthesis of Intermediate 2

[0027] 44.6 g (0.1 mol) of intermediate 1a, 34.7 g (0.5 mol) of hydroxylamine hydrochloride, and 446 mL of methanol were mixed. The pH of the reaction system was adjusted to 4-5 with pyridine, the mixture was purged with nitrogen, and the mixture was refluxed for 24 h. The mixture was concentrated to dryness, 100 mL of water was added, and the mixture was extracted with ethyl acetate, dried, and concentrated to dryness. Heptane was added to induce crystallization, and the crystals were filtered and dried to give 30.4 g of compound 2a as a white solid, with a yield of 66%.

[0028] Example 4: Synthesis of Intermediate 2

[0029] 44.6 g (0.1 mol) of intermediate 1a, 34.7 g (0.5 mol) of hydroxylamine hydrochloride, and 446 mL of methanol were mixed. The pH of the reaction system was adjusted to 4-5 with pyridine, the mixture was purged with nitrogen, and the mixture was refluxed for 24 h. The mixture was concentrated to dryness, 100 mL of water was added, and the mixture was extracted with ethyl acetate, dried, and concentrated to dryness. Heptane was added to crystallize the mixture, and the crystals were filtered and dried to give 30.4 g of compound 2a as a white solid, with a yield of 66%.

[0030] Example 5: Synthesis of intermediate 3 hydrochloride

[0031]

[0032] 23 g (0.05 mol) of compound 2a, 10.7 g (0.2 mol) of ammonium chloride, 6.5 g (0.1 mol) of zinc powder, and 230 mL of methanol were mixed. Under nitrogen protection, the mixture was refluxed for 4 h, cooled, filtered, and washed with methanol. The filtrate was concentrated to dryness, ethyl acetate was added, and the mixture was washed with water. The organic phase was dried, and 0.1 mol of hydrogen chloride-ethyl acetate was added. The mixture was stirred at room temperature for 1 h, precipitating a large amount of solid. The solid was filtered and dried to give 20 g of compound 3a hydrochloride, a white solid, with a yield of 83%. MS(ESI)[M+H] + =447.3; 1 H NMR (400MHz, CD3OD) δ8.94(d,J=5.1Hz,1H),8.58(d,J=7.9Hz,1H),8.24–8.09(m,1H),7.30(ddd,J=14.5,9.0,3.7Hz,3H),5.76(dd,J=9.6,3.6 Hz,1H),5.57(d,J=9.8Hz,1H),3.53(s,1H),2.44–2.21(m,2H),2.00(dd,J=12.4,8.8Hz,2H),1.43(dt,J=14.9,7.5Hz,3H),1.21–1.12(m,18H).

[0033] Example 6: Synthesis of intermediate 3 hydrochloride

[0034] 23 g (0.05 mol) of compound 2a, 1.15 g (catalytic amount) of Raney nickel, and 230 mL of ethanol were mixed, purged with hydrogen, pressurized to 80 Psi, and reacted at 40 °C for 20 h. After cooling, the mixture was filtered and washed with ethanol. Hydrogen chloride-ethanol (0.1 mol) was added, and the mixture was stirred at room temperature for 1 h. A large amount of solid precipitated, which was filtered and dried to give 18.6 g of compound 3a hydrochloride, a white solid, with a yield of 77%.

[0035] Example 7: Synthesis of Intermediate 3

[0036] 23 g (0.05 mol) of compound 2a, 1.15 g (catalytic amount) of 5% palladium on carbon, and 230 mL of ethanol were mixed, purged with hydrogen, pressurized to 120 Psi, and reacted at 50 °C for 20 h. After cooling, the mixture was filtered and washed with ethanol. Hydrogen chloride-ethanol (0.1 mol) was added, and the mixture was stirred at room temperature for 1 h. A large amount of solid precipitated, which was filtered and dried to give 18.1 g of compound 3a hydrochloride, a white solid, with a yield of 75%.

[0037] The above are merely preferred embodiments of the present invention. It should be noted that the above preferred embodiments should not be considered as limitations on the present invention, and the scope of protection of the present invention should be determined by the scope defined in the claims. For those skilled in the art, several improvements and modifications can be made without departing from the spirit and scope of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A process for the preparation of an intermediate for the CGRP receptor antagonist rimelglurant, characterized by, The reaction is represented by the following equation: ； wherein R is selected from TBS or TIPS.

2. The process for the preparation of an intermediate for the CGRP receptor antagonist rimelglurant according to claim 1, characterized in that, The process comprises the following steps: using compound 1 as raw material, reacting with hydroxylamine hydrochloride in an organic solvent to generate intermediate 2, and then reacting in the presence of a reducing agent to obtain remegedipam intermediate 3.

3. The process for the preparation of an intermediate for the CGRP receptor antagonist rimelglurant according to claim 2, characterized in that: The organic solvent is selected from methanol, ethanol or isopropanol.

4. The process for the preparation of an intermediate for the CGRP receptor antagonist rimelglurant according to claim 2, characterized in that: The molar ratio of compound 1 to hydroxylamine hydrochloride is 1:1-8.

5. The process for the preparation of an intermediate for the CGRP receptor antagonist rimelglurant according to claim 2, characterized in that: In the first step, an organic base is added to the reaction; the organic base is selected from pyridine or DMAP.

6. The process for the preparation of an intermediate for the CGRP receptor antagonist rimelglurant according to claim 2, characterized in that: The reducing agent is selected from zinc powder, Raney nickel or palladium on carbon.

7. The process for the preparation of an intermediate for the CGRP receptor antagonist rimelglurant according to claim 6, characterized in that: The zinc powder forms a reducing system with the acid; Raney nickel or palladium on carbon needs to be pressurized to 60-150 psi in the presence of hydrogen.

8. The process for the preparation of an intermediate for the CGRP receptor antagonist rimelglurant according to claim 2, characterized in that: After the second step reaction, hydrochloric acid or hydrogen chloride solution is added to generate remegedipam intermediate 3 hydrochloride.

Images