Preparation method of chiral intermediate of avacopane

Abstract

This invention provides a method for preparing the chiral intermediate compound of formula I, which features a novel route design that avoids the chiral resolution process used in existing technologies. This method is highly practical, yields high output, reacts rapidly, and produces few byproducts, making it very suitable for industrial applications. The structural formula of compound I is as follows: where R1 is fluorine; R2 is COR4; and R4 is a methoxy group.

Description

Technical Field

[0001] This invention relates to avacopan, and more specifically to a method for preparing avacopan chiral intermediate. Background Technology

[0002] Avacopan, developed by Chimosentex Corporation, is a drug for the treatment of severe active antineutrophilic cytoplasmic antibody-associated vasculitis (SAV). SAV is a rare, systemic autoimmune disease affecting small blood vessels. For decades, glucocorticoids were used to treat SAV. While treatment methods have improved patient outcomes, long-term use of hormones has led to organ damage and other toxicities that threaten patient health. Phase III clinical trial data for avacopan showed that its 26-week remission rate was similar to prednisone, while its 52-week sustained remission rate was significantly better than prednisone. Therefore, avacopan can reduce or even replace glucocorticoid use, ushering in a new era for the treatment of SAV.

[0003] The structure of the avacopane is as follows:

[0004]

[0005] CN106999481A discloses a method for preparing avocadopa, which is not only lengthy in its preparation steps, but also requires resolution with benzoyl-L-tartaric acid, resulting in a low yield of the final product. Summary of the Invention

[0006] To address the problems in the prior art, the present invention provides a compound (Formula I) that can be used as a raw material or intermediate for the synthesis of avacopan.

[0007] Unless otherwise specified, all parts mentioned in this invention are parts by weight, and all percentages are mass percentages.

[0008] To achieve the above objectives, the technical solution of the present invention is as follows:

[0009] Compound I has the following structural formula:

[0010]

[0011] Where R1 is fluorine; R2 is COR4; and R4 is methoxy.

[0012] In one embodiment, the present invention also provides the use of the compound of formula I as a raw material or intermediate for avacopan.

[0013] In one embodiment, compound I may appear as an impurity in the avacopan final product, therefore the present invention also provides the use of compound I as a reference standard for impurities in avacopan.

[0014] Compound II has the following structural formula:

[0015]

[0016] Where R1 is fluorine; R2 is COR4; R3 is nitro; and R4 is methoxy.

[0017] In one embodiment, the compound of formula II may appear as an impurity in the final product of the compound of formula I, and therefore the present invention also provides the use of the compound of formula II as a reference for impurities of the compound of formula I.

[0018] In one embodiment, the compound of formula I of the present invention is obtained by reduction of the compound of formula II.

[0019] The reduction of compound II to compound I involves two chiral positions and also requires nitro reduction. Studies have shown that different catalysts and ligands significantly affect the reaction; poor control can lead to numerous byproducts, low yields, and low ee values. Furthermore, reaction conditions also influence the product yield and ee value. After extensive experimentation, the inventors discovered that using rhodium bis(1,5-cyclooctadiene)tetrafluoroborate (I)(Rh(COD)2BF4) as a catalyst, (R)-Ligand 1 as the catalyst ligand, and dichloromethane as the solvent, reacting at 20-30°C under hydrogen at 1 atmosphere for 12-24 hours resulted in fewer byproducts, a higher yield of the final product (compound II), and a higher ee value.

[0020] The structural formula of (R)-Ligand 1 described in this invention is:

[0021]

[0022] In one embodiment, the compound of formula II of the present invention is prepared by coupling the compound of formula III and the compound of formula IV, as shown in the following reaction formula:

[0023]

[0024] In one embodiment, the preparation method of compound II of the present invention is as follows: compound III is dissolved in anhydrous acetone, K2CO3 and DMF solution containing compound IV are added, and the reaction is stirred at room temperature for 30-40 hours. Then anhydrous Na2SO4 is added, and the reaction is continued at 40-60°C for 2-5 hours. Then compound II is separated.

[0025] In one embodiment, compound IV is prepared by reacting compound VI and compound V, as shown in the following reaction formula:

[0026]

[0027] In one embodiment, the preparation method of compound IV of the present invention is as follows: compound V (2-fluoro-6-methylbenzoic acid) is dissolved in anhydrous THF, and after cooling to -5 to 0°C in a low-temperature reaction tank, a THF solution of oxaloyl chloride is added dropwise. After the addition is complete, the mixture is moved to room temperature and stirred for 1-3 hours. After the reaction system is cooled to -5 to 0°C, a THF solution containing pyridine and compound VI is added dropwise. After the addition is complete, the mixture is moved to room temperature and stirred for another 3-5 hours. Compound IV is then separated.

[0028] The preparation method of compound III is as follows: under nitrogen protection, a THF solution containing methyl chloroformate is added dropwise to a THF solution containing NaH and p-nitroacetophenone, and then the mixture is refluxed for 2-4 hours. After the reaction system is cooled to room temperature, the reaction is terminated with acetic acid, and compound III is obtained by separation.

[0029] Beneficial effects:

[0030] This invention provides a compound (Formula I) that can be used as a raw material or intermediate for the synthesis of avacopan. The entire route of this invention is novel, avoiding the chiral resolution process used in existing technologies. It is highly practical, with high yield, fast reaction rate, and few byproducts, making it very suitable for industrial applications. This invention uses rhodium bis(1,5-cyclooctadiene)tetrafluoroborate (I)(Rh(COD)2BF4) as a catalyst, (R)-Ligand 1 as the catalyst ligand, and dichloromethane as a solvent. The compound of formula II is prepared by chiral reduction in hydrogen at 1 atmosphere at 20-30°C for 12-24 hours. The final product has a high yield and a high ee value. This invention yields the avacopan intermediate of formula I through a three-step reaction, with an overall yield of up to 63.59% (based on 2-fluoro-6-methylbenzoic acid). In summary, the preparation method of this invention is simple, the raw materials are inexpensive and readily available, the reaction conditions are mild, large-scale equipment is not required, and the final product has a high yield and high purity, making it suitable for industrial production. Detailed Implementation

[0031] The present invention will now be described in detail through specific embodiments. It should be noted that these embodiments are only for further illustration and should not be construed as limiting the scope of protection of the present invention. Those skilled in the art can make some non-essential improvements and adjustments to the present invention based on the above description. All raw materials and reagents used in this invention are commercially available products.

[0032] Example 1: Synthesis of Compound I

[0033] The reaction route for the reduction of compound II (R1 is fluorine; R2 is COR4; R3 is nitro; R4 is methoxy) to prepare compound I (R1 is fluorine; R2 is COR4; R4 is methoxy) is as follows:

[0034]

[0035] In a reaction flask containing 20 mL of dichloromethane with bis(1,5-cyclooctadiene)tetrafluoroborate (I) (Rh(COD)₂BF₄, 81 mg, 0.2 mmol) and ligand (R)-Ligand 1 (174 mg, 0.4 mmol), a solution of 4 g (10 mmol) of compound II in isopropanol (40 mL) was added. The mixture was then stirred at room temperature under hydrogen atmosphere at 1 atm for 18 hours, and TLC showed that the reaction was complete. The reaction solution was diluted with 200 mL of ethyl acetate and then washed with saturated aqueous solutions of NaHCO₃ (100 mL x 2) and saturated aqueous solutions of NaCl (100 mL x 2), respectively. The organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 5) to give 3.6 g of compound I as a white solid, yield 96%, ee value 98.8%. H1 NMR (400MHz, CDCl3): δ (ppm): 7.52 (m, 1H), 7.32-6.99 (m, 4H), 6.61 (m, 2H), 4.18 (m, 1H), 3.76 (s, 3H ),3.61-3.32(m,4H),2.88(m,1H),2.46(s,3H),2.12(m,1H),1.78-1.61(m,3H).MS(m / z)371(M+1).

[0036] Example 2 Synthesis of Compound II

[0037] Compound II (R1 is fluorine; R2 is COR4; R3 is nitro; R4 is methoxy) is prepared by coupling compound III (R2 is COR4; R3 is nitro; R4 is methoxy) and compound IV (R1 is fluorine), as shown in the following reaction:

[0038]

[0039] 4.9 g (22 mmol) of compound III was dissolved in 100 mL of anhydrous acetone, followed by the addition of 4.2 g (30 mmol) of K₂CO₃ and 5.5 g (20 mmol) of compound IV in 10 mL of DMF solution. The mixture was stirred at room temperature for 36 hours, then 5 g of anhydrous Na₂SO₄ was added, and the mixture was stirred at 50 °C for another 3 hours. TLC showed the reaction was complete. The residue after concentration under reduced pressure was added to 200 mL of ethyl acetate, washed with saturated NaCl (100 mL x 2) aqueous solution, and the organic layer was dried over anhydrous Na₂SO₄. The concentrated crude product was separated by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10) to give 6.3 g of compound II as a yellow solid, yield 72%. H1 NMR (400MHz, CDCl3): δ (ppm): 8.38 (d, J = 8.7Hz, 2H), 8.01 (d, J = 8.7Hz, 2H), 7.51 (m, 1H), 7.3 1-7.03(m,2H),3.87-3.60(m,5H),2.79-2.52(m,5H),1.78-1.55(m,2H).MS(m / z)399(M+1).

[0040] Example 3 Synthesis of Compound IV

[0041] Compound IV (R1 is fluorine) is prepared by reacting compound VI and compound V (R1 is fluorine), as shown in the following reaction formula:

[0042]

[0043] In a dry 250 mL three-necked flask equipped with a magnetic stirrer, 50 mL of anhydrous THF, 0.2 mL of anhydrous DMF, and 3.1 g (20 mmol) of compound V (2-fluoro-6-methylbenzoic acid) were added. The mixture was cooled to 0 °C in a cryogenic reaction vessel, and then a 15 mL solution of THF containing 1.7 mL (20 mmol) oxalyl chloride was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 2 hours. After cooling the reaction system to 0 °C, a 20 mL solution of THF containing 1.7 mL (40 mmol) pyridine and 2.8 g (20 mmol) of compound VI was added dropwise. After the addition was complete, the mixture was stirred at room temperature for another 4 hours. TLC showed that the reaction was complete. Dilute with 200 mL of ethyl acetate, wash with water (100 mL x 2), 2 M NaOH aqueous solution (100 mL x 2), saturated NaHCO3 aqueous solution (100 mL x 2), and saturated NaCl aqueous solution (100 mL x 2), respectively. The organic layer was dried over anhydrous Na2SO4 and concentrated to give 5 g of compound IV, a white solid, with a yield of 92%. 1NMR (400MHz, CDCl3): δ (ppm): 9.12 (s, 1H), 7.43 (m, 1H), 7.21-6.96 (m, 2H), 3. 55-3.39(m,4H),2.38(s,3H),2.20-2.14(m,2H).MS(m / z)274(M+1),276(M+1).

[0044] Example 4: Synthesis of Compound III (2-fluoro-6-methylbenzoic acid)

[0045] In a 150 mL three-necked flask equipped with magnetic stirring and nitrogen protection, 1.2 g (20 mmol, 60%) of NaH and 3.3 g (20 mmol) of p-nitroacetophenone in 40 mL of THF solution were added. Then, under magnetic stirring, 20 mL of THF solution containing 2.1 g (22 mmol) of methyl chloroformate was added dropwise over approximately 10 minutes. The mixture was refluxed under magnetic stirring for 3 hours, and TLC showed that the reaction was complete. The reaction system was cooled to room temperature, and the reaction was terminated with acetic acid. The mixture was diluted with 200 mL of ethyl acetate, washed with saturated NaCl aqueous solution (100 mL x 4), dried over Na2SO4, and concentrated. The crude product was separated by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 20) to give 3.2 g of compound III as a yellow solid, with a yield of 72%. 1 NMR (400MHz, CDCl3): Enol δ (ppm): 12.22 (s, 1H), 8.32 (d, J = 8.9Hz, 2H), 7.96 (d, J = 8.9Hz, 2H), 5.78 (s, 1H), 3.84 (s, 3H). MS (m / z): 224 (M+1).

Claims

1. A method for preparing the compound of formula I, characterized in that: Compound II is reduced to give compound I; the reaction route is as follows: ； R1 is fluorine; R2 is COR4; R3 is nitro; R4 is methoxy; the catalyst used for reduction is rhodium di(1,5-cyclooctadiene)tetrafluoroborate, and the ligand of the catalyst is (R)-Ligand 1; the reaction solvent is dichloromethane, and the reaction is carried out in hydrogen at 1 atmosphere at 20-30°C for 12-24 hours; the structural formula of (R)-Ligand 1 is: ； Compound II is prepared by coupling compound III and compound IV, as shown in the following reaction formula: ； Compound III was dissolved in anhydrous acetone, and K2CO3 and DMF solution containing compound IV were added. After reacting at room temperature for 30-40 hours, anhydrous Na2SO4 was added, and the reaction was continued at 40-60℃ for 2-5 hours. Then, compound II was obtained by separation.

2. The preparation method according to claim 1, characterized in that: Compound IV is prepared by reacting compound VI and compound V, as shown in the following reaction formula: ； Compound V was dissolved in anhydrous THF, and the reaction tank was cooled to -5~0 o C, and a THF solution of oxalyl chloride was added dropwise. After the addition was completed, the reaction tank was moved to room temperature and reacted for 1-3 hours. The reaction system was cooled to -5~0 o C, and a THF solution containing pyridine and compound VI was added dropwise. After the addition was completed, the reaction tank was moved to room temperature and reacted for 3-5 hours. Compound IV was separated.

3. The preparation method according to claim 2, characterized in that, The preparation method of compound III is as follows: under nitrogen protection, a THF solution containing methyl chloroformate is added dropwise to a THF solution containing dissolved NaH and p-nitroacetophenone, and then refluxed for 2-4 hours. After the reaction system is cooled to room temperature, the reaction is terminated with acetic acid, and compound III is obtained by separation.

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