Method for preparing CGRP receptor antagonist intermediate

Abstract

The invention discloses a method for preparing a CGRP receptor antagonistic intermediate, and belongs to the field of synthesis of medical intermediates. A compound 1 is adopted as a raw material and reacts with hydroxylamine hydrochloride in an organic solvent to generate an intermediate 2, and then the intermediate 2 reacts in the presence of a reducing agent to obtain a remegapam intermediate 3. The key point of the invention is that the R substituent group in the compound 1 adopts a large-steric-hindrance silicon group, so that the highly specific stereoselectivity during the reduction reaction is ensured. The key intermediate obtained by the method has high chiral purity, is simple and convenient to operate, and can realize later industrial production of the variety.

Description

Technical Field

[0001] The invention relates to a method for preparing a CGRP receptor antagonist intermediate, and belongs to the field of pharmaceutical intermediate synthesis. Background Art

[0002] Rimegepant is an oral CGRP receptor antagonist developed by Biohaven Pharmaceuticals for the acute treatment of migraine in adults. As a targeted CGRP drug, Rimegepant blocks the binding of CGRP to its receptors, reduces the activity of the trigeminovascular system, and inhibits acute migraine attacks. It is the first targeted CGRP drug that has been proven to be effective in both acute and preventive treatment of migraine. On February 27, 2020, it was approved for marketing by the U.S. Food and Drug Administration (FDA).

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

[0004] A. Transaminase catalysis method, i.e., using transaminase to asymmetrically synthesize the intermediate 3 of the amination product under ammonia source conditions. The use of enzyme catalysis for asymmetric preparation has outstanding advantages such as high conversion rate, good stereoselectivity, mild reaction conditions and environmental friendliness. However, this method has the disadvantages of difficulty in obtaining enzymes, difficulty in preserving enzyme activity and catalytic ability, and the application of most enzyme-catalyzed reactions is one-time, which makes it difficult to reuse and results in high costs; and high requirements for equipment and cumbersome operation.

[0005] B. Amination reduction method, i.e., isopropyl titanate is aminated under ammonia pressure of 100 Psi, and then hydrogenated and reduced under Pd / Al2O3 catalysis and pressure of 100 Psi to obtain the product intermediate 3. The amination reduction method is used for amination and asymmetric hydrogenation, and the required ammonia is highly polluting to the environment and has high requirements for personnel protection; the hydrogenation method has low safety and is not conducive to large-scale preparation and industrial production.

[0006] Therefore, there is an urgent need in the art to develop a method for preparing a key intermediate of Remigipan that is low in cost, simple to operate, high in yield and suitable for industrial production. Summary of the invention

[0007] In order to overcome the above technical defects, the present invention provides a method for synthesizing a key intermediate of Remigipam to solve the shortcomings of the existing methods at this stage proposed by the above background technology. The core technical solution is to use compound 1 as a raw material, react with hydroxylamine hydrochloride in an organic solvent to generate intermediate 2, then react in the presence of a reducing agent to obtain Remigipam intermediate 3; then react with hydrochloric acid or hydrogen chloride to generate Remigipam intermediate 3 hydrochloride.

[0008] The method for preparing the remegipam intermediate 3 of the present invention is represented by the following reaction equation:

[0009]

[0010] Wherein: R is a sterically hindered silicon protecting group.

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

[0012] Furthermore, in the above technical solution, the bulky sterically hindered silicon protecting group 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 the 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 carbon.

[0017] Furthermore, in the above technical solution, the zinc powder and the acid form a reduction system; the Raney nickel or palladium 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 the remegipam intermediate 3 hydrochloride.

[0019] Advantageous Effects of the Invention

[0020] The key of the present invention is that the R substituent in compound 1 adopts a large sterically hindered silicon group to ensure highly specific stereoselectivity during the reduction reaction. The key intermediate obtained by the method of the present invention has high chiral purity and is easy to operate, and can realize the industrial production of this variety in the later stage. DETAILED DESCRIPTION

[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, replaced with nitrogen, and refluxed at high temperature for 24 h; concentrated to dryness, added with 100 mL of water, extracted with ethyl acetate, dried, and concentrated to dryness; n-heptane was added for crystallization, filtered and dried to obtain 29 g of compound 2a as a white solid with a yield of 63%.

[0024] Example 2: Synthesis of Intermediate 2

[0025] Mix 44.6 g (0.1 mol) of intermediate 1a, 34.7 g (0.5 mol) of hydroxylamine hydrochloride, and 446 mL of ethanol, adjust the reaction system pH to 4-5 with DMAP, replace with nitrogen, and reflux for 24 h; concentrate to dryness, add 100 mL of water, extract with ethyl acetate, dry, and concentrate to dryness; add n-heptane for crystallization, filter and dry to obtain 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 atmosphere was replaced with nitrogen, and the reaction was refluxed at elevated temperature for 24 h; the mixture was concentrated to dryness, 100 mL of water was added, the mixture was extracted with ethyl acetate, dried, and concentrated to dryness; n-heptane was added for crystallization, and the mixture was filtered and dried to obtain 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 atmosphere was replaced with nitrogen, and the mixture was heated to reflux for 24 h; the mixture was concentrated to dryness, 100 mL of water was added, the mixture was extracted with ethyl acetate, dried, and concentrated to dryness; n-heptane was added for crystallization, and the mixture was filtered and dried to obtain 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] Compound 2a 23g (0.05mol), ammonium chloride 10.7g (0.2mol), zinc powder 6.5g (0.1mol) and 230mL methanol were mixed, nitrogen protection, heated to reflux for 4h, cooled, filtered, and washed with methanol; the filtrate was concentrated to dryness, ethyl acetate was added, and washed with water; the organic phase was dried, hydrogen chloride-ethyl acetate (0.1mol) was added, and stirred at room temperature for 1h, a large amount of solid precipitated, filtered, and dried to obtain 20g of compound 3a hydrochloride as 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, replaced with hydrogen, pressurized to 80 Psi, kept at 40°C for 20 h, cooled, filtered, and washed with ethanol; hydrogen chloride-ethanol (0.1 mol) was added, stirred at room temperature for 1 h, a large amount of solid precipitated, filtered, and dried to obtain 18.6 g of compound 3a hydrochloride as 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, replaced with hydrogen, pressurized to 120 Psi, kept at 50°C for 20 h, cooled, filtered, and washed with ethanol; hydrogen chloride-ethanol (0.1 mol) was added, stirred at room temperature for 1 h, a large amount of solid precipitated, filtered, and dried to obtain 18.1 g of compound 3a hydrochloride as a white solid, with a yield of 75%.

[0037] The above are only preferred embodiments of the present invention. It should be noted that the above preferred embodiments should not be regarded as limiting the present invention, and the protection scope of the present invention should be based on the scope defined by the claims. For ordinary technicians in this technical field, 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 regarded as the protection scope of the present invention.

Claims

1. A method for preparing a CGRP receptor antagonist remigipam intermediate, characterized in that: The reaction equation is expressed as follows: Wherein: R is a sterically hindered silicon protecting group.

2. The method for preparing a remigipam intermediate according to claim 1, characterized in that: The bulky sterically hindered silicon protecting group is selected from TBS or TIPS.

3. The method for preparing a remegipam intermediate according to claim 1 or 2, characterized in that: The method comprises the following steps: using compound 1 as a raw material, reacting with hydroxylamine hydrochloride in an organic solvent to generate an intermediate 2, and then reacting in the presence of a reducing agent to obtain a remegipam intermediate 3.

4. The method for preparing a remegipam intermediate according to claim 3, characterized in that: The organic solvent is selected from methanol, ethanol or isopropanol.

5. The method for preparing a remegipam intermediate according to claim 3, characterized in that: The molar ratio of the compound 1 to hydroxylamine hydrochloride is 1:1-8.

6. The method for preparing a remegipam intermediate according to claim 3, characterized in that: In the first step, an organic base is added to the reaction; the organic base is selected from pyridine or DMAP.

7. The method for preparing a remegipam intermediate according to claim 3, characterized in that: The reducing agent is selected from zinc powder, Raney nickel or palladium carbon.

8. The method for preparing a remegipam intermediate according to claim 7, characterized in that: The zinc powder and the acid form a reduction system; the Raney nickel or palladium carbon needs to be pressurized to 60-150 psi in the presence of hydrogen to react.

9. The method for preparing a remegipam intermediate according to claim 3, characterized in that: After the second step reaction is completed, hydrochloric acid or hydrogen chloride solution is added to generate the remegipam intermediate 3 hydrochloride.

Images