Process for the preparation of an ensitrelvir intermediate

Abstract

The application discloses a preparation method of an Ensitrelvir intermediate, and the method comprises the following steps: 1-(bromomethyl)-4-chloro-2-nitrobenzene of a compound of formula II is subjected to a substitution reaction to obtain 1-(4-chloro-2-nitrophenyl)-N-methylmethanamine of a compound of formula III; 1-(4-chloro-2-nitrophenyl)-N-methylmethanamine of the compound of formula III is subjected to reduction and cyclization to obtain 6-chloro-2-methyl-2H-indazole of a compound of formula IV; 6-chloro-2-methyl-2H-indazole of the compound of formula IV is subjected to a nitration reaction to obtain 6-chloro-2-methyl-5-nitro-2H-indazole of a compound of formula V; and 6-chloro-2-methyl-5-nitro-2H-indazole is reduced to 6-chloro-2-methyl-2H-indazol-5-amine of a compound of formula V. The technical scheme of the application uses 1-methyl-4-chloro-2-nitrobenzene which is easy to obtain as a starting material, reduces the cost of preparation, obtains the Ensitrelvir intermediate through substitution, reduction and cyclization, avoids using diazotization to improve the safety of the reaction, avoids using methylation to improve the yield of the intermediate, avoids using isomer separation and purification to improve the yield of the intermediate, and reduces the cost of industrial production.

Description

Technical Field

[0001] This invention relates to the field of drug synthesis, and specifically to a method for preparing an Ensitrelvir intermediate. Background Technology

[0002] 6-Chloro-2-methyl-2H-indazole-5-amine and its corresponding salts are important intermediates for the oral COVID-19 drug Ensitrelvir. Ensitrelvir was developed by Shionogi & Co., Ltd. of Japan and is used for the treatment of COVID-19.

[0003]

[0004] 6-Chloro-2-methyl-2H-indazole-5-amine

[0005] The existing reported methods for synthesizing 6-chloro-2-methyl-2H-indazole-5-amine and its corresponding salts mainly use 5-chloro-2-methyl-4-nitroaniline as the starting material, construct an indazole ring through a diazotization reaction, and then prepare it through a methylation reaction and a reduction reaction.

[0006]

[0007]

[0008] This synthetic route has drawbacks such as safety risks associated with diazotization, poor regioselectivity in methylation reactions, difficulty in isomer separation and purification, low overall yield, and high industrial production costs. Summary of the Invention

[0009] To address the aforementioned problems, this invention discloses a method for preparing an Ensitrelvir intermediate. This method uses readily available raw materials, is low in cost, safe to operate, has a high overall yield, and low industrial production costs.

[0010] The technical solution of the present invention is as follows: A method for preparing an Ensitrelvir intermediate includes the following steps:

[0011] (1) Compound II, 1-(bromomethyl)-4-chloro-2-nitrobenzene, is substituted to give compound III, 1-(4-chloro-2-nitrophenyl)-N-methylmethylamine; (2) Compound 1-(4-chloro-2-nitrophenyl)-N-methylmethylamine of Formula III was reduced and cyclized to obtain compound 6-chloro-2-methyl-2H-indazole of Formula IV; (3) Compound IV, 6-chloro-2-methyl-2H-indazole, is nitrated to give compound V, 6-chloro-2-methyl-5-nitro-2H-indazole; (4) Compound V of formula 6-chloro-2-methyl-5-nitro-2H-indazole is reduced to 6-chloro-2-methyl-2H-indazole-5-amine.

[0012] Furthermore, in step (1), compound II 1-(bromomethyl)-4-chloro-2-nitrobenzene undergoes a substitution reaction with methylamine.

[0013] Further, in step (2), compound III 1-(4-chloro-2-nitrophenyl)-N-methylmethylamine is dissolved in an organic solvent, and zinc powder and ammonium formate are added to react.

[0014] Furthermore, the molar ratio of compound III 1-(4-chloro-2-nitrophenyl)-N-methylmethylamine to zinc powder is 1:3 to 6. A preferred molar ratio is 1:4 to 6, and an even more preferred molar ratio is 1:5.

[0015] Furthermore, the molar ratio of compound III 1-(4-chloro-2-nitrophenyl)-N-methylmethylamine to ammonium formate is 1:1 to 1.5. The preferred molar ratio is 1:1.

[0016] Further, in step (3), 6-chloro-2-methyl-2H-indazole is dissolved in concentrated sulfuric acid, cooled in an ice bath, and concentrated nitric acid is slowly added dropwise to control the temperature of the reaction.

[0017] Further, in step (4), 6-chloro-2-methyl-5-nitro-2 H - Indazole is dissolved in ethanol, then water, iron powder and ammonium chloride are added, and the reaction proceeds.

[0018] Furthermore, the compound of formula II, 1-(bromomethyl)-4-chloro-2-nitrobenzene, is derived from compound of formula I, 1-methyl-4-chloro-2-nitrobenzene, chloroform, N It is prepared by reacting bromosuccinimide with azobisisobutyronitrile. .

[0019] Compared with the prior art, the present invention has the following technical effects: Using readily available 1-methyl-4-chloro-2-nitrobenzene as the starting material reduces the preparation cost. The Ensitrelvir intermediate is obtained through substitution, reduction, and cyclization. Diazotization is avoided to improve the safety of the reaction, methylation is avoided to improve the yield of the intermediate, and isomer separation and purification are avoided to improve the yield of the intermediate, thereby reducing the cost of industrial production. Specific Implementation To further illustrate the technical means and effects of this invention, the following embodiments are provided for further explanation. It should be understood that the specific embodiments described herein are merely illustrative of the invention and not intended to limit it.

[0021] Where specific techniques or conditions are not specified in the examples, they shall be performed in accordance with the techniques or conditions described in the literature in this field, or in accordance with the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased through legitimate channels.

[0022]

[0023] Under nitrogen protection, 1-methyl-4-chloro-2-nitrobenzene (29.1 mmol, 1 eq, 5 g) and chloroform (25 mL) were added to a three-necked flask, stirred until dissolved, and then added... N 1-Bromosuccinimide (45.0 mmol, 1.2 eq, 6.3 g) was heated to reflux, and then azobisisobutyronitrile (2.9 mmol, 0.1 eq, 480 mg) was added. The reaction was continued under reflux with stirring for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was washed with 30 mL of a 1:4 (v / v) mixture of ethyl acetate and n-heptane, filtered, and the filter cake was washed once more with 20 mL of a 1:4 (v / v) mixture of ethyl acetate and n-heptane. The organic phases were combined and concentrated under reduced pressure to give a yellow oily compound 1-(bromomethyl)-4-chloro-2-nitrobenzene (7.5 g crude product), which was used directly in the next reaction without further purification. 1 H NMR (400 MHz, CDCl3) d 8.05 (d, J = 2.0 Hz, 1H), 7.59 (dd, J =8.4, 2.0 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 4.79 (s, 2H).

[0024]

[0025] Add 7 ml of 40% methylamine aqueous solution to a three-necked flask, then add dropwise a solution of 1-(bromomethyl)-4-chloro-2-nitrobenzene (29.1 mmol, 1 eq, 7.5 g crude product) dissolved in isopropanol (10 ml) under ice bath conditions, keeping the temperature below 30 °C during the addition. After the addition is complete, stir at room temperature for 2 hours. After the reaction is complete, concentrate under reduced pressure to remove isopropanol, then add 30 ml of water to the residue, adjust the pH to ≈1 with 6N hydrochloric acid, and extract three times with ethyl acetate (20 ml * 3). Then adjust the pH of the aqueous phase to ≈10 with 10% sodium hydroxide, and extract three times with ethyl acetate (20 ml * 3). Combine the organic phases and concentrate under reduced pressure to give 3.8 g of pale yellow solid 1-(4-chloro-2-nitrophenyl)-N-methylmethylamine, with a two-step yield of 65%. LCMS (ESI) m / z = 201.1 [M+H] + .

[0026] Example 3: 6-Chloro-2-methyl-2 H Synthesis of -indazole

[0027] 1-(4-chloro-2-nitrophenyl)-N-methylmethylamine (18.9 mmol, 1 eq, 3.8 g) was dissolved in methanol (20 ml), and zinc powder (94.5 mmol, 5 eq, 6.1 g) was added. Ammonium formate (18.9 mmol, 1 eq, 1.2 g) was added dropwise in methanol (10 ml) under ice bath conditions, maintaining the temperature below 20 °C. After the addition was complete, the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was filtered through diatomaceous earth. The filter cake was washed once with methanol (10 ml). The organic phases were combined and concentrated under reduced pressure. Water (20 ml) was added to the residue, and the mixture was extracted three times with ethyl acetate (20 ml * 3). The organic phases were combined and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate / n-heptane = 1:4 (v / v) to give a pale yellow solid, 6-chloro-2-methyl-2-methylamine. H -Indazole 2.2 g, yield 70%. LCMS (ESI) m / z = 167.1 [M+H] + ; 1 H NMR (400 MHz, CDCl3) d 7.88 (s, 1H), 7.68 (d, J = 2.0, 1H), 7.57 (d, J = 8.8, Hz, 1H), 7.03 (dd, J = 8.8, 2.0 Hz, 1H), 4.20 (s, 3H).

[0028] Example 4: 6-Chloro-2-methyl-5-nitro-2 H Synthesis of -indazole

[0029] 6-chloro-2-methyl-2 H 13.2 mmol, 1 eq, 2.2 g of indazole was dissolved in concentrated sulfuric acid (7 ml), cooled to below 10 °C in an ice bath, and then concentrated nitric acid (3 ml) was slowly added dropwise, with the temperature controlled below 10 °C during the addition. After the addition was complete, the mixture was stirred in an ice bath for 1 hour. After the reaction was complete, the reaction mixture was slowly poured into crushed ice (20 g), and a solid precipitated. The solid was filtered, and the filter cake was washed once with pure water (10 ml) and dried under vacuum to give a pale yellow solid, 6-chloro-2-methyl-5-nitro-2- H -Indazole 2.3 g, yield 83%. LCMS (ESI) m / z = 212.1 [M+H] + ; 1 H NMR (400 MHz, CDCl3) d 8.33 (s, 1H), 8.14 (s, 1H), 7.83 (s, 1H), 4.28 (s, 3H); 13 C NMR (400 MHz, CDCl3) d 148.6, 143.4, 127.2, 123.2, 120.1, 119.9, 118.8, 41.1.

[0030] Example 5: 6-Chloro-2-methyl-2 H Synthesis of 5-indazole-5-amine

[0031] 6-chloro-2-methyl-5-nitro-2 H -Indazole (10.9 mmol, 1 eq, 2.3 g) was dissolved in ethanol (10 ml), then water (5 ml), iron powder (43.6 mmol, 4 eq, 2.4 g), and ammonium chloride (10.9 mmol, 1 eq, 580 mg) were added. The mixture was heated to 80 °C and stirred for 2 hours. After the reaction was complete, the reaction system was filtered through diatomaceous earth. The filter cake was washed twice with ethyl acetate (10 ml) with stirring. The filtrates were combined and concentrated under reduced pressure. Water (20 ml) was added to the residue, and the mixture was extracted three times with ethyl acetate (20 ml * 3). The organic phases were combined and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate / n-heptane = 1:4 (v / v) to give a white solid 6-chloro-2-methyl-2- H2.2 g of 6-indazole-5-amine, yield 70%. The mixture was slowly poured into crushed ice (20 g), causing a solid to precipitate. The solid was filtered, and the filter cake was washed once with pure water (10 ml). The solution was then vacuum dried to give a pale yellow solid, 6-chloro-2-methyl-5-nitro-2-amine. H -Indazole 1.7g, yield 86%. LCMS (ESI) m / z = 182.1 [M+H] + ; 1 H NMR (400 MHz, CDCl3) d 7.69 (s, 1H), 7.62 (s, 1H), 6.89 (s, 1H), 4.13 (s, 3H); 13 C NMR (400 MHz, CDCl3) d 145.1,137.6, 124.4, 121.8, 121.4, 117.4, 100.7, 40.2.

[0032] The applicant declares that the detailed method of the present invention is illustrated by the above embodiments, but the present invention is not limited to the above detailed method, that is, it does not mean that the present invention must rely on the above detailed method to be implemented. Those skilled in the art should understand that any improvements to the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A method for preparing an Ensitrelvir intermediate, characterized in that: Includes the following steps: (1) Compound II, 1-(bromomethyl)-4-chloro-2-nitrobenzene, was substituted to give compound III, 1-(4-chloro-2-nitrophenyl)-N-methylmethylamine; (2) Compound III, 1-(4-chloro-2-nitrophenyl)-N-methylmethylamine, was reduced and cyclized to give compound IV, 6-chloro-2-methyl-2H-indazole; (3) Compound IV, 6-chloro-2-methyl-2H-indazole, was nitrated to give compound V, 6-chloro-2-methyl-5-nitro-2H-indazole; (4) Compound V of formula 6-chloro-2-methyl-5-nitro-2H-indazole is reduced to 6-chloro-2-methyl-2H-indazole-5-amine.

2. The preparation method according to claim 1, characterized in that: In step (1), compound II 1-(bromomethyl)-4-chloro-2-nitrobenzene undergoes a substitution reaction with methylamine.

3. The preparation method according to claim 1, characterized in that: In step (2), compound III 1-(4-chloro-2-nitrophenyl)-N-methylmethylamine is dissolved in an organic solvent, and zinc powder and ammonium formate are added to react.

4. The preparation method according to claim 3, characterized in that: The molar ratio of compound III 1-(4-chloro-2-nitrophenyl)-N-methylmethylamine to zinc powder is 1:3 to 6.

5. The preparation method according to claim 4, characterized in that: The molar ratio of compound III 1-(4-chloro-2-nitrophenyl)-N-methylmethylamine to ammonium formate is 1:1 to 1.

5.

6. The preparation method according to claim 1, characterized in that: In step (3), 6-chloro-2-methyl-2H-indazole is dissolved in concentrated sulfuric acid, cooled in an ice bath, and concentrated nitric acid is slowly added dropwise to control the temperature of the reaction.

7. The preparation method according to claim 1, characterized in that: In step (4), 6-chloro-2-methyl-5-nitro-2H-indazole is dissolved in ethanol, and then water, iron powder and ammonium chloride are added to react.

8. The preparation method according to any one of claims 1-7, characterized in that: The compound of formula II, 1-(bromomethyl)-4-chloro-2-nitrobenzene, was prepared by reacting compound of formula I, 1-methyl-4-chloro-2-nitrobenzene, with chloroform, N-bromosuccinimide, and azobisisobutyronitrile.

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