Process for the preparation of enfuvirtide intermediates

Abstract

The application discloses a preparation method of an intermediate of Ensitavir, and the method comprises the following steps: a compound of formula V is subjected to a reduction and a cyclization reaction to obtain a compound of formula VI; and the compound of formula VI is subjected to a reaction to obtain a compound of formula VII, 6-chloro-2-methyl-2H-indazole-5-amine; wherein R is H, an alkyl group, a halogenated alkyl group, an aromatic group, an aromatic heterocyclic group, and the technical scheme of the application uses 3-nitro-4-chlorobenzaldehyde or 2-chloro-5-methylaniline which is easy to obtain and cheaper as a starting material, adopts a safer reaction operation, and is used for preparing an important intermediate of a new oral drug of Ensitavir, 6-chloro-2-methyl-2H-indazole-5-amine and a corresponding salt thereof, with a higher total yield; the use of diazotization is avoided to improve the safety of the reaction, the use of isomer separation and purification is avoided to improve the yield of the intermediate, the methylation reaction of isomers is avoided to improve the yield of the intermediate, the cost of preparation and industrial production is reduced, and the method is more suitable for industrial production.

Description

[Technical Field]

[0001] This invention relates to the field of drug synthesis, and more specifically to a method for preparing an intermediate of ensetvir. [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, which was developed by Shionogi & Co., Ltd. of Japan for the treatment of COVID-19.

[0003]

[0004] 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.

[0005]

[0006] 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]

[0007] To address the aforementioned problems, this invention discloses a method for preparing an ensetvir intermediate. This method uses readily available raw materials, is low in cost, and is safe to operate. The methylation selectivity of this invention is high, the overall yield is high, and the industrial production cost is low.

[0008] The technical solution of the present invention is as follows:

[0009] A method for preparing an ensetvir intermediate includes the following steps:

[0010]

[0011] (1) Compound V of formula V undergoes reduction and cyclization reactions to obtain compound VI of formula V;

[0012] (2) The compound of formula VI was reacted to obtain the compound of formula VII, 6-chloro-2-methyl-2H-indazole-5-amine;

[0013] Wherein, R is H, alkyl, haloalkyl, aromatic, aromatic heterocyclic,

[0014] Furthermore, it also includes:

[0015]

[0016] (3) Compound II of formula is reacted to obtain compound V of formula.

[0017] Further, step (3) includes:

[0018]

[0019] (3-1) Compound II of formula is reacted to give compound IV of formula;

[0020] (3-2) Compound IV of formula IV is reacted to obtain compound V of formula V;

[0021] Wherein, R1 is H, alkyl, haloalkyl, aromatic, aromatic heterocyclic,

[0022] Further, in step (3-2), compound IV of formula is dissolved in an organic solvent, and an aqueous solution of methylamine is added to react.

[0023] Further, step (3-1) includes:

[0024]

[0025] (3-1-1) Compound II of formula II reacts to give compound III of formula III;

[0026] (3-1-2) Compound III of formula is reacted to give compound IV of formula.

[0027] Further, in step (3-1-1), the compound of formula II is dissolved in an organic solvent, and a catalyst is added dropwise to initiate the reaction. The preferred catalyst is 4-dimethylaminopyridine.

[0028] Further, in step (3-1-2), compound III is dissolved in an organic solvent, a brominating agent is added, and a reaction is carried out.

[0029] Further, in step (1), compound V is dissolved in an organic solvent, and zinc powder and ammonium formate are added to react.

[0030] Further, in step (2), compound VI is dissolved in an organic solvent, and then sodium hydroxide is added to react.

[0031] Furthermore, compound II is prepared by reacting compound I with concentrated sulfuric acid and concentrated nitric acid.

[0032]

[0033] Furthermore, compound I is composed of compound VIII, 2-chloro-5-methylaniline, and The reaction was prepared to obtain,

[0034]

[0035] Furthermore, it also includes:

[0036]

[0037] (4) Compound III-1 is reacted to obtain compound V.

[0038] Further, step (4) includes:

[0039]

[0040] (4-1) Compound III-1 is nitrated to give compound IV-1;

[0041] (4-2) Compound IV-1 is reacted to obtain compound V.

[0042] Further, in step (4-1), the compound of formula III-1 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.

[0043] Further, in step (4-2), compound IV-1 is dissolved in an organic solvent, cooled in an ice bath, and an aqueous solution of methylamine is added, followed by a temperature-controlled reaction.

[0044] Furthermore, compound III-1 is composed of compound II-1, 3-amino-4-chlorobenzaldehyde, and The reaction was prepared to obtain,

[0045]

[0046] Furthermore, compound II-1 is prepared by adding iron powder to water, followed by dropwise addition of a solution of compound I-1, 3-nitro-4-chlorobenzaldehyde, dissolved in ethyl acetate and acetic acid, under controlled temperature.

[0047]

[0048] Compared with the prior art, the present invention has the following technical effects:

[0049] Using readily available and cheaper 3-nitro-4-chlorobenzaldehyde or 2-chloro-5-methylaniline as starting materials, and employing safer reaction procedures, this study prepares 6-chloro-2-methyl-2H-indazole-5-amine and its corresponding salt, an important intermediate for the oral COVID-19 drug Ensetvir, with a higher overall yield. It avoids diazotization to improve reaction safety, isomer separation and purification to increase intermediate yield, and methylation of isomers to increase intermediate yield, thus reducing preparation and industrial production costs and making it more suitable for industrial production. [Image Description]

[0050] Figure 1 The hydrogen spectrum of the original material in Example 1;

[0051] Figure 2 The photon spectrum of the product of Example 3 is shown. [Specific Implementation Examples]

[0052] To further illustrate the technical means and effects of this invention, the following description, in conjunction with embodiments and accompanying drawings, provides a further explanation of the invention. It is understood that the specific embodiments described herein are merely illustrative of the invention and not intended to limit it.

[0053] 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.

[0054] Example 1: Synthesis of 3-amino-4-chlorobenzaldehyde

[0055]

[0056] Iron powder (431.2 mmol, 4 eq, 24.1 g) was added to water (80 ml), and the temperature was raised to 50 °C. While stirring, a solution of 3-nitro-4-chlorobenzaldehyde (107.8 mmol, 1 eq, 20 g) dissolved in ethyl acetate (40 ml) and acetic acid (40 ml) was added dropwise, maintaining the temperature below 70 °C during the addition. After the addition was complete, the reaction was continued at 70 °C with stirring for 2 hours. The reaction was stopped after the starting material disappeared as monitored by LCMS. The mixture was filtered while hot, and the filter cake was washed with ethyl acetate with stirring. The mixture was separated, and the aqueous phase was extracted three times with ethyl acetate (100 ml * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 15.3 g of 3-amino-4-chlorobenzaldehyde, with a yield of 91%. LCMS (ESI) m / z = 156.1 [M + H] + ;

[0057] Example 2: Synthesis of N-(2-chloro-5-formylphenyl)acetamide

[0058]

[0059] Add 3-amino-4-chlorobenzaldehyde (98.3 mmol, 1 eq, 15.3 g), triethylamine (1.5 eq, 14.9 g), and dichloromethane (70 mL) to a three-necked flask, stir until dissolved, and add acetyl chloride (1.3 eq, 10.0 g) dropwise under ice bath. After the addition is complete, continue stirring under ice bath for 1 hour, and then add 100 mL of water to terminate the reaction. Separate the liquid and aqueous phases, extract once with dichloromethane (100 mL), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to give 18.1 g of yellow solid N-(2-chloro-5-formylphenyl)acetamide, yield: 93%. LCMS (ESI) m / z = 198.1 [M+H] + .

[0060] Example 3: Synthesis of N-(2-chloro-5-formyl-4-nitrophenyl)acetamide

[0061]

[0062] N-(2-chloro-5-formylphenyl)acetamide (91.6 mmol, 1 eq, 18.1 g) and concentrated sulfuric acid (40 mL) were added to a three-necked flask and stirred until dissolved. The mixture was then cooled to below 10 °C in an ice bath, and concentrated nitric acid (10 mL) was slowly added dropwise, with the temperature controlled below 10 °C during the addition. After the addition was complete, the reaction mixture was stirred in an ice bath for 8 hours. The reaction mixture was then slowly poured into 150 g of crushed ice, and a solid precipitated. The solid was filtered, and the filter cake was washed once with 50 mL of ice water. The solid was dried under vacuum to obtain 16.2 g of a yellow solid, N-(2-chloro-5-formyl-4-nitrophenyl)acetamide, with a yield of 73%. LCMS (ESI) m / z = 243.1 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ10.44(s,1H),9.00(s,1H),8.24(s,1H),7.88(s,1H),2.33(s,3H).

[0063] Example 4: Synthesis of N-(2-chloro-5-((methylamino)methyl)-4-nitrophenyl)acetamide

[0064]

[0065] N-(2-chloro-5-formyl-4-nitrophenyl)acetamide (66.8 mmol, 1 eq, 16.2 g) and methanol (50 mL) were added to a three-necked flask and stirred until dissolved. The mixture was cooled to below 10 °C in an ice bath, and then 40% methylamine aqueous solution (100.2 mmol, 1.5 eq, 7.8 g) was added dropwise, with the temperature controlled below 20 °C during the addition. After the addition was complete, the reaction was stirred in an ice bath for 2 hours. Then, sodium borohydride (50.1 mmol, 0.75 eq, 1.9 g) was added in portions, with the temperature controlled below 20 °C during the addition. After the addition was complete, the reaction was stirred in an ice bath for 0.5 hours. After monitoring the starting material with LCMS, 100 mL of water was added to terminate the reaction. The mixture was concentrated under reduced pressure to remove methanol. The aqueous phase was extracted three times with ethyl acetate (100 mL * 3). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was dissolved again in 100 ml of ethyl acetate, and the pH was adjusted to approximately 1 with concentrated hydrochloric acid. A solid precipitated, which was filtered. The filter cake was washed once with 20 ml of ethyl acetate and dried under vacuum to give 23.5 g of a yellow solid, 1-(4-chloro-3-nitrophenyl)-N-methylmethylamine hydrochloride, with a yield of 90%. LCMS (ESI) m / z = 258.1 [M+H] + .

[0066] Example 5: Synthesis of 6-chloro-2-methyl-2H-indazole-5-acetamide

[0067]

[0068] N-(2-chloro-5-((methylamino)methyl)-4-nitrophenyl)acetamide (15.6 mmol, 1 eq, 4.0 g) was dissolved in methanol (40 mL), and zinc powder (4 eq, 2 g) and ammonium formate (1 eq, 1 g) were added. The mixture was stirred at room temperature for 12 h. After the reaction was complete, the mixture was filtered through diatomaceous earth. The filter cake was washed once with ethyl acetate (30 mL), and water (50 mL) was added to the filtrate. The mixture was separated, and the aqueous phase was extracted once with ethyl acetate (50 mL). The organic phases were combined and concentrated under reduced pressure to give 3.1 g of a yellow solid, 6-chloro-2-methyl-2H-indazole-5-acetamide, with a yield of 90%. LCMS (ESI) m / z = 224.1 [M+H] + .

[0069] Example 6: Synthesis of 6-chloro-2-methyl-2H-indazole-5-amine

[0070]

[0071] 6-Chloro-2-methyl-2H-indazole-5-acetamide (13.4 mmol, 1 eq, 3.0 g) was dissolved in ethanol (20 mL), and sodium hydroxide (2 eq, 1.0 g) was added. The mixture was refluxed and stirred for 2 hours. After the reaction was complete, the reaction mixture was filtered through a diatomaceous earth filter. 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 2.2 g of white solid 6-chloro-2-methyl-2H-indazole-5-amine, yield 70%. LCMS (ESI) m / z = 182.1 [M+H] + ; 1 HNMR (400MHz, CDCl3) δ7.69(s,1H),7.62(s,1H),6.89(s,1H),4.13(s,3H); 13 C NMR (400MHz, CDCl3) δ145.1,137.6,124.4,121.8,121.4,117.4,100.7,40.2.

[0072] Example 7: Synthesis of N-(2-chloro-5-methylphenyl)acetamide

[0073]

[0074] 2-Chloro-5-methylaniline (211.9 mmol, 1 eq, 30 g), triethylamine (1.5 eq, 32.1 g), and dichloromethane (150 mL) were added to a three-necked flask and stirred until dissolved. Acetyl chloride (1.3 eq, 21.6 g) was added dropwise under ice bath conditions. After the addition was complete, the reaction was stirred under ice bath conditions for 1 hour, and the reaction was terminated by adding 100 mL of water. The mixture was separated, and the aqueous phase was extracted once with dichloromethane (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 35.1 g of a yellow solid, N-acetyl-N-(2-chloro-5-methyl-4-nitrophenyl)acetamide, yield: 90%. LCMS (ESI) m / z = 184.1 [M+H] + .

[0075] Example 8: Synthesis of N-(2-chloro-5-methyl-4-nitrophenyl)acetamide

[0076]

[0077] N-(2-chloro-5-methylphenyl)acetamide (190.6 mmol, 1 eq, 35 g) and concentrated sulfuric acid (70 mL) were added to a three-necked flask and stirred until dissolved. The mixture was cooled to below 10 °C in an ice bath, and then concentrated nitric acid (25 mL) was slowly added dropwise, with the temperature controlled to not exceed 20 °C during the addition. After the addition was complete, the reaction mixture was stirred in an ice bath for 2 hours. The reaction mixture was then slowly poured into 150 g of crushed ice, and a solid precipitated. The solid was filtered, and the filter cake was washed once with 100 mL of ice water. The solid was dried under vacuum to obtain 35.5 g of yellow solid N-(2-chloro-5-methyl-4-nitrophenyl)acetamide, yield: 81%. LCMS (ESI) m / z = 229.6 [M+H] +

[0078] Example 9: Synthesis of N-acetyl-N-(2-chloro-5-methyl-4-nitrophenyl)acetamide

[0079]

[0080] To a three-necked flask, add N-(2-chloro-5-methyl-4-nitrophenyl)acetamide (43.7 mmol, 1 eq, 10 g), triethylamine (1.5 eq, 6.6 g), 4-dimethylaminopyridine (0.5 eq, 0.5 g), and dichloromethane (38 mL). Stir until dissolved, then add acetic anhydride (1.5 eq, 6.7 g) dropwise at room temperature. After the addition is complete, stir at room temperature for 2 hours, then add 50 mL of water to terminate the reaction. Separate the solutions; extract the aqueous phase once with dichloromethane (30 mL), and combine the organic phases. Add 10 mL of ethyl acetate to the crude product, heat to reflux until completely dissolved, then add 40 mL of n-heptane, slowly cool to room temperature, and precipitate a solid. Filter, dry, and give 9.6 g of yellow solid N-acetyl-N-(2-chloro-5-methyl-4-nitrophenyl)acetamide, yield: 81%. LCMS(ESI)m / z = 271.7[M+H] + .

[0081] Example 10: Synthesis of N-acetyl-N-(5-(bromomethyl)-2-chloro-4-nitrophenyl)acetamide

[0082]

[0083] N-acetyl-N-(2-chloro-5-methyl-4-nitrophenyl)acetamide (18.5 mmol, 1 eq, 5 g), N-bromosuccinamide (1.5 eq, 4.9 g), azobisisobutyronitrile (0.5 eq, 1.5 g), and 80 g of carbon tetrachloride were added to a three-necked flask, and the mixture was refluxed and stirred for 12 h. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated to dryness to give 5.8 g of brown solid N-acetyl-N-(5-benzylbromo-2-chloro-4-nitrophenyl)acetamide, yield: 90%. LCMS (ESI) m / z = 348.9 [M+H] + .

[0084] Example 11: Synthesis of N-(2-chloro-5-((methylamino)methyl)-4-nitrophenyl)acetamide

[0085]

[0086] N-acetyl-N-(5-(bromomethyl)-2-chloro-4-nitrophenyl)acetamide (18.7 mmol, 1 eq, 6.5 g) was dissolved in acetonitrile (50 mL), and 15 g of 40% methylamine aqueous solution was slowly added dropwise at room temperature, with stirring at room temperature for 2 h. After the reaction was complete, the solution was concentrated to dryness under reduced pressure to obtain a brown oily liquid. 100 mL of water was added, and the mixture was stirred until homogeneous. The pH was adjusted to 1–2 with 6N hydrochloric acid. Extraction was performed with methyl tert-butyl ether (100 mL). The organic phases were combined to give 4.0 g of yellow solid N-(5-benzylmethylamino-2-chloro-4-nitrophenyl)acetamide, yield: 83%. LCMS (ESI) m / z = 258.1 [M+H] + .

[0087] 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 ensetvir intermediate, characterized in that, Includes the following steps: (1) Compound V is reduced and cyclized to obtain compound VI; (2) The compound of formula VI was reacted to give the compound of formula VII, 6-chloro-2-methyl-2H-indazole-5-amine; Wherein, R is an alkyl group.

2. The preparation method according to claim 1, characterized in that, Also includes: The following steps (3) Compound II of formula is reacted to obtain compound V of formula.

3. The preparation method according to claim 2, characterized in that, Step (3) includes: (3-1) Compound II of formula reacts to give compound IV; (3-2) Compound IV reacts to yield compound V; Wherein, R1 is an alkyl group; Step (3-1) includes: (3-1-1) Compound II of formula II reacts to give compound III of formula III; (3-1-2) Compound III of formula is reacted to give compound IV of formula.

4. The preparation method according to claim 3, characterized in that, In step (3-2), compound IV is dissolved in an organic solvent, and an aqueous solution of methylamine is added to react.

5. The preparation method according to any one of claims 1 to 4, characterized in that: In step (1), compound V is dissolved in an organic solvent, and zinc powder and ammonium formate are added to react. In step (2), compound VI is dissolved in an organic solvent, and then sodium hydroxide is added to react.

6. The preparation method according to any one of claims 2 to 4, characterized in that: Compound II is prepared by reacting compound I with concentrated sulfuric acid and concentrated nitric acid. 。 7. The preparation method according to claim 6, characterized in that, Compound I is composed of compound VIII, 2-chloro-5-methylaniline, and The reaction was prepared to obtain, 。 8. The preparation method according to claim 1, characterized in that, Also includes: (4) Compound III-1 reacts to yield compound V; Step (4) includes: (4-1) Compound III-1 is nitrated to give compound IV-1; (4-2) Compound IV-1 is reacted to obtain compound V.

9. The preparation method according to claim 8, characterized in that, In step (4-1), compound III-1 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. In step (4-2), compound IV-1 is dissolved in an organic solvent, cooled in an ice bath, and then an aqueous solution of methylamine is added, followed by a temperature-controlled reaction.

10. The preparation method according to claim 8 or 9, characterized in that, Compound III-1 is composed of compound II-1, 3-amino-4-chlorobenzaldehyde, and The reaction was prepared to obtain, 。 11. The preparation method according to claim 10, characterized in that, Compound II-1 was prepared by adding iron powder to water, followed by dropwise addition of a solution of 3-nitro-4-chlorobenzaldehyde (compound I-1) dissolved in ethyl acetate and acetic acid, under controlled temperature. 。 12. Compound III of general formula, in, R is an alkyl group; R1 is an alkyl group.

13. Compound of general formula IV, in, R is an alkyl group; R1 is an alkyl group.

14. Compound V, of general formula in, R stands for alkyl group.

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