A method for preparing a pharmaceutical intermediate

Abstract

The application discloses a preparation method of a medical intermediate, in particular a preparation method of 6-chloro-2-methyl-5-nitro-2H-indazole, wherein the yield of the target product can reach 50%-65%, the synthesis route is relatively short, the reagent cost is relatively low, the reaction condition is mild, the method is safe and environment-friendly, and the method is suitable for industrial production. The method can be used for producing an anti-COVID-19 candidate compound S-217622 and related intermediates, and is favorable for promoting pharmaceutical production.

Description

Technical Field

[0001] This invention relates to the field of chemical and pharmaceutical technology, and specifically to a method for preparing a pharmaceutical intermediate. Background Technology

[0002] The pathogen of COVID-19 is the novel coronavirus (SARS-CoV-2), which belongs to the genus β-coronavirus of the family Coronaviridae. It is a type of enveloped single-stranded positive-sense RNA virus.

[0003] Yuto Unoh et al. disclosed that the candidate compound S-217622 ((E)-6-((6-chloro-2-methyl-2H-indazol-5-yl)imino)-3-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazinane-2,4-dione) could be used to treat COVID-19 (Yuto Unoh et al., “Discovery of S-217622, ​​a Noncovalent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19”, J. Med. Chem., 2022). 6-Chloro-2-methyl-2H-indazole-5-amine (CAS:1893125-36-4) is an important intermediate in the preparation of S-217622, ​​and it is also a synthetic intermediate for other important compounds (such as the indazole compounds of IRAK4 inhibitors described in WO2015104662A1).

[0004] Patent document CN114605328A discloses a method for preparing 6-chloro-2-methyl-2H-indazole-5-amine, and its main synthetic route is as follows:

[0005]

[0006] The synthetic route is relatively long. In the step of methylating 6-chloro-5-nitro-1H-indazole, the methylating agent used is trimethyloxonium tetrafluoroboric acid, which is quite expensive and will greatly increase the production cost.

[0007] Example 10 of patent document WO2015104662A1 discloses a step of methylating 6-chloro-5-nitro-2H-indazole using sodium hydride and iodomethane. This step has a low product yield (only 44%), and sodium hydride and iodomethane are highly toxic. Sodium hydride has high chemical reactivity and is prone to spontaneous combustion, resulting in low safety and operability. Summary of the Invention

[0008] To overcome the shortcomings of the prior art, the present invention provides a method for preparing pharmaceutical intermediates and their applications.

[0009] In a first aspect of the present invention, a method for preparing a compound of formula I is provided, comprising the following steps:

[0010] (1) Mix the compound shown in Formula II with a solvent;

[0011] (2) Add acid;

[0012] (3) Add a methylating agent and proceed with the reaction;

[0013] Optionally, (4) post-processing;

[0014]

[0015] Where X is a halogen.

[0016] Specifically, X can be fluorine, chlorine, bromine, or iodine; in one embodiment of the invention, X is chlorine.

[0017] Specifically, the solvent in step (1) can be a non-polar solvent. Preferably, the non-polar solvent is n-hexane, cyclohexane, n-heptane, chloroform, toluene, or THF, etc. More preferably, the solvent is toluene or THF, especially toluene.

[0018] Specifically, the mass-to-volume ratio of the compound shown in Formula II to the solvent can be 1:1-10 (e.g., 1:1, 1:2, 1:4, 1:5, 1:6, 1:8, 1:9, 1:10) (w / v, in g:ml); in one embodiment of the present invention, the mass-to-volume ratio is 1:5.

[0019] In a preferred embodiment of the present invention, the acid in step (2) is sulfuric acid, such as concentrated sulfuric acid (98%).

[0020] Specifically, the molar ratio of the compound shown in Formula II to the acid can be 1:0.2-2 (e.g., 1:0.2, 1:0.4, 1:0.6, 1:0.8, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.8, 1:2), where the raw material cannot be completely consumed if the acid equivalent is insufficient; preferably, the molar ratio is 1:0.8-2, particularly 1:1.1-1.5; in one embodiment of the present invention, the molar ratio is 1:1.1.

[0021] Specifically, the method of adding acid in step (2) can be dropwise addition.

[0022] Specifically, the addition of acid in step (2) can be carried out at 20-30°C (e.g., room temperature).

[0023] In a preferred embodiment of the present invention, the methylating agent in step (2) is trimethyl orthoformate.

[0024] Specifically, the molar ratio of the compound shown in Formula II to the methylating agent can be 1:1-10 (e.g., 1:1, 1:2, 1:4, 1:5, 1:6, 1:8, 1:9, 1:10); in one embodiment of the present invention, the molar ratio is 1:8.

[0025] In a preferred embodiment of the invention, the methylating agent is added in batches, for example, 1 eq (relative to the compound shown in Formula II) of the methylating agent is added every 30 minutes; specifically, each batch of the methylating agent can be added dropwise. Batch addition can simultaneously avoid excessively high local concentrations, accelerate the reaction process, and reduce the formation of impurities.

[0026] In a more preferred embodiment of the present invention, step (3) involves adding trimethyl orthoformate dropwise in batches to carry out the reaction.

[0027] Specifically, the temperature at which the methylating agent is added and the reaction occurs in step (3) is 30-90°C (e.g., 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90°C). At this temperature, the reaction rate can be kept relatively fast while the generation of impurities can be reduced. Preferably, the temperature is 45-80°C. In one embodiment of the present invention, the temperature is 60°C.

[0028] Specifically, the reaction time in step (3) can be 1-6 hours (e.g., 1, 2, 3, 4, 5, 6 hours).

[0029] Specifically, the post-processing in step (4) includes (4a): cooling the reaction system obtained in step (3) (e.g., to 0°C), (e.g., adding a saturated sodium carbonate aqueous solution), adjusting the pH to alkaline, and separating the insoluble matter.

[0030] In one embodiment of the invention, the method of separating insoluble matter is filtration, such as vacuum filtration.

[0031] Specifically, step (4) further includes (4b): allowing the liquid obtained after separating the insoluble matter (e.g., filtrate) to stand, and extracting the aqueous layer with an organic solvent.

[0032] In one embodiment of the present invention, the organic solvent used for the extraction is ethyl acetate.

[0033] Specifically, step (4b) further includes: washing and concentrating the organic phase obtained from the extraction to obtain a crude product.

[0034] In one embodiment of the present invention, the solvent used for washing the organic layer is a saturated sodium chloride aqueous solution.

[0035] Specifically, step (4) may also include (4c): further purifying the crude product obtained in step (4b), for example, by pulping in an organic solvent.

[0036] Specifically, the pulping solvent can be a non-polar solvent. Preferably, the non-polar solvent is n-hexane, cyclohexane, n-heptane, chloroform, toluene, THF, etc. More preferably, the solvent is toluene or THF, and most preferably toluene.

[0037] In a second aspect of the invention, a method for preparing a compound of formula III is provided, comprising the steps of the method described in the first aspect, and further comprising a step of nitro-reducing the compound of formula I.

[0038]

[0039] In one embodiment of the invention, nitro reduction is carried out using ammonium chloride and iron powder.

[0040] In a third aspect of the invention, a method for preparing a compound of formula IV or a salt thereof is provided, comprising the steps of the method described in the second aspect, and further comprising a step of reacting a compound of formula V with a compound of formula III.

[0041]

[0042] in,

[0043] Y represents a halogen;

[0044] n is an integer from 1 to 5;

[0045] R1 and R2 are each independently C1-C6 alkyl groups.

[0046] Specifically, Y can be fluorine, chlorine, bromine, or iodine; in one embodiment of the present invention, Y is chlorine.

[0047] Specifically, n can be 1, 2, 3, 4, or 5; in one embodiment of the present invention, n is 3.

[0048] Specifically, R1 can be a C1-C3 alkyl group; in one embodiment of the present invention, R1 is a methyl group.

[0049] Specifically, R2 can be a C1-C3 alkyl group; in one embodiment of the present invention, R2 is an ethyl group.

[0050] Specifically, the reaction of the compound shown in Formula V with the compound shown in Formula III can be carried out in the presence of a base (e.g., LHMDS) (e.g., as described in Yuto Unoh et al., “Discovery of S-217622, ​​a Noncovalent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19”, J. Med. Chem., 2022).

[0051] In one embodiment of the present invention, the compound represented by Formula IV has the following structure:

[0052]

[0053] In a fourth aspect of the invention, the method described in the first aspect is provided for use in the preparation of compounds of formula III, compounds of formula IV, and medicaments for treating diseases caused by coronaviruses in subjects.

[0054] In one embodiment of the present invention, the coronavirus is a novel coronavirus (SARS-CoV-2).

[0055] In one embodiment of the invention, the subject is a person, such as a child, an adult, or an elderly person.

[0056] Through extensive experimental screening and optimization, this invention provides a method for preparing pharmaceutical intermediates, particularly a method for preparing 6-chloro-2-methyl-5-nitro-2H-indazole. The method achieves a target product yield of 50%-65%, reduces reaction impurities, has a shorter synthetic route, lower reagent costs, milder reaction conditions, and is safe and environmentally friendly, making it suitable for industrial production. This method can be used to produce the anti-COVID-19 candidate compound S-217622 and its related intermediates, which will facilitate its pharmaceutical production. Attached Figure Description

[0057] Figure 1 The results shown are from the TLC analysis of Example 1, with the developing solvent being PE and EA at a ratio of 1:1.

[0058] Figure 2 The figure shown is an HPLC chromatogram of the product obtained in Example 1. Detailed Implementation

[0059] Unless otherwise defined, all scientific and technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art.

[0060] The term "halogen" refers to fluorine, chlorine, bromine, and iodine, especially bromine, chlorine, or fluorine, preferably chlorine or fluorine.

[0061] The term "C1-C6 alkyl" refers to a straight-chain or branched alkyl group having a specific number of carbon atoms (e.g., one, two, three, four, five, or six carbon atoms), such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl.

[0062] The compounds mentioned in this application may exist in free form, such as as a free base, a free acid, or a zwitterion, or in the form of a salt. The salt may be any salt commonly used in pharmaceuticals, an organic or inorganic addition salt, and particularly any physiologically acceptable organic or inorganic addition salt.

[0063] The term "subject" refers to an animal, including but not limited to primates (e.g., humans), monkeys, cattle, pigs, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. Specifically, the subject is 0 years or older, 1 year or older, 2 years or older, 4 years or older, 5 years or older, 10 years or older, 12 years or older, 13 years or older, 15 years or older, 16 years or older, 18 years or older, 20 years or older, 25 years or older, 30 years or older, 35 years or older, 40 years or older, 45 years or older, 50 years or older, 55 years or older, 60 years or older, 65 years or older, 70 years or older, 75 years or older, 80 years or older, 85 years or older, 90 years or older, 95 years or older, 100 years or older, or 105 years or older.

[0064] The term "coronavirus" belongs to the genus Coronavirus in the family Coronaviridae. One variant of coronavirus is the pathogen that causes atypical pneumonia. Coronaviruses include, but are not limited to, the 2019 novel coronavirus (2019-nCoV or SARS-CoV-2, causing COVID-19), HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV (causing severe acute respiratory syndrome), and MERS-CoV (causing Middle East respiratory syndrome). Diseases caused by coronaviruses are primarily respiratory infections (including severe acute respiratory syndrome, SARS).

[0065] The term "novel coronavirus" refers to the 2019 novel coronavirus (2019-nCoV) or SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) published by the International Committee on Taxonomy of Viruses in February 2020. In this application, SARS-CoV-2 and 2019-nCoV have the same meaning, and also include all variants of the 2019 novel coronavirus, such as all variants included in NCBI or GISAID (Global Initiative on Sharing All Influenza Data), especially important variants with strong transmissibility, pathogenicity, or immune evasion, such as the WHO-designated Alpha, Beta, Gamma, Delta, Eta, Iota, Kappa, or Lambda variants, and subsequently designated important variants.

[0066] All publications, patents, and published patent specifications cited in this article are incorporated herein in their entirety through citation.

[0067] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0068] The reaction formulas for the methylation reaction of 6-chloro-5-nitro-2H-indazole involved in the following examples are shown below:

[0069]

[0070] The S-SM4-4 isomer mentioned in the following examples refers to its 1-methyl isomer (6-chloro-1-methyl-5-nitro-1H-indazole), with the following structure:

[0071] The S-SM4-3 isomer mentioned in the following examples refers to 6-chloro-5-nitro-1H-indazole, with the following structure:

[0072] Example 1

[0073] (1) Reaction steps

[0074] Add 100g of S-SM4-3 and 500ml of dry toluene to a three-necked flask and stir until well mixed. Add sulfuric acid dropwise at room temperature. Heat to 60℃ and add trimethyl orthoformate dropwise in portions, adding 1 eq of trimethyl orthoformate every 30 min. After the addition is complete, allow the reaction to proceed for 2 h. As the reaction continues, the reaction solution gradually turns red and clear. Monitor the reaction by TLC until it is complete, and the content of the S-SM4-4 isomer in the reaction solution is less than 10% (e.g., ...). Figure 1 (As shown in the table below). The amounts of reactants fed into the reaction are shown in the table below.

[0075] Table 1 Feeding Amount

[0076] Feeding amount m / V n Mole ratio weight ratio S-SM4-3 100g 0.51 1 1 Trimethyl orthoformate 429.7g 4.05 8 0.73 Sulfuric acid (98%) 55.7g 0.56 1.1 0.56 Toluene 500ml 5V 0.44

[0077] (2) Post-processing

[0078] After the reaction was complete, the mixture was cooled to 0°C in an ice bath. A saturated sodium carbonate aqueous solution was added to adjust the pH to alkaline. The mixture was mechanically stirred for 10 min, precipitating a large amount of insoluble matter. This was filtered to obtain a yellow solid (containing less than 1% of the S-SM4-3 and S-SM4-4 isomers). The filtrate was allowed to stand and separate into layers. The aqueous layer was extracted with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride aqueous solution. The organic layer was concentrated to obtain a red solid (containing less than 5% of the S-SM4-3 and S-SM4-4 isomers). The obtained solid was purified by slurrying with toluene. The yield was 63%, and the purity was 95.5%. The HPLC chromatogram of the obtained product is shown below. Figure 2 As shown.

[0079] Example 2

[0080] Referring to the experimental conditions of Example 1, the solvent was replaced with THF. TLC showed that there were fewer quaternary ammonium salt impurities, and the content of the target product in the standard curve quantitative reaction solution reached 60%.

[0081] Example 3

[0082] Referring to the experimental conditions of Example 1, the reaction temperature was adjusted to 80°C. TLC showed that there were fewer quaternary ammonium salt impurities, and the content of the target product in the standard curve quantitative reaction solution reached 58%.

[0083] Referring to the experimental conditions of Example 1, the reaction temperature was adjusted to 30°C. TLC showed that there were fewer quaternary ammonium salt impurities, and the content of the target product in the standard curve quantitative reaction solution reached 52%.

[0084] Comparative Example 1: Selection of Methylating Agent

[0085] (1) Using S-SM4-3 as reactant, methylation was performed using iodomethane and potassium carbonate system. The main product was the S-SM4-4 isomer with methyl at position 1. The content of the target product, S-SM4-4 with methyl at position 2, in the reaction solution was less than 30%.

[0086] (2) Referring to the experimental conditions of Example 1, the methylating agent was replaced with dimethylpropane, which mainly generated the S-SM4-3 isomer and almost no target product S-SM4-4 was generated.

[0087] Comparative Example 2: Solvent Selection

[0088] (1) Referring to the experimental conditions of Example 1, the solvent was replaced with acetone. The main product obtained was the S-SM4-4 isomer, which had poor selectivity.

[0089] (2) Referring to the experimental conditions of Example 1, the solvent was replaced with DMF. The reaction rate was very slow. The standard curve showed that the raw material consumption was large and the product increase was small. Nearly 50% of the raw material was converted into quaternary ammonium salt.

[0090] Comparative Example 3: Choice of Acid

[0091] (1) Referring to the experimental conditions of Example 1, sulfuric acid was replaced with formic acid, and there was basically no reaction.

[0092] (2) Referring to the experimental conditions of Example 1, sulfuric acid was replaced with trifluoroacetic acid, and there was basically no reaction.

[0093] (3) Referring to the experimental conditions of Example 1, sulfuric acid was replaced with hydrochloric acid, and there was basically no reaction.

[0094] (4) Referring to the experimental conditions of Example 1, sulfuric acid was replaced with p-toluenesulfonic acid, which can react at a higher temperature, but also produces more quaternary ammonium salt impurities.

[0095] Comparative Example 4: Selection of Reaction Temperature

[0096] (1) Referring to the experimental conditions of Example 1, trimethyl orthoformate was added dropwise under toluene reflux. The reaction rate was very fast, but quaternary ammonium salt impurities were generated quickly. As the reaction proceeded, a large number of quaternary ammonium salt impurities were generated.

[0097] (2) Referring to the experimental conditions of Example 1, the reaction temperature was replaced with 0℃, and there was basically no reaction; when the temperature was raised to room temperature, quaternary ammonium salt impurities were obviously produced as the reaction proceeded.

[0098] Comparative Example 5: Selection of Acid Dosage

[0099] Referring to the experimental conditions of Example 1, the amount of acid was replaced with 0.2 eq and increased. The reaction monitoring showed that when the acid equivalent was insufficient, the raw material could not be completely consumed. As the acid was added, the raw material was gradually consumed completely.

[0100] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

[0101] The foregoing embodiments and methods described in this invention may vary based on the capabilities, experience, and preferences of those skilled in the art.

[0102] The fact that the steps of the method are listed in a certain order in this invention does not constitute any restriction on the order of the method steps.

Claims

1. A method for preparing a compound of Formula I, comprising the following steps: (1) Mix the compound shown in Formula II with a solvent; (2) Add acid; (3) Add a methylating agent and proceed with the reaction; (4) Post-processing; in, X is a halogen; The solvent mentioned in step (1) is toluene or THF; The acid mentioned in step (2) is sulfuric acid, and the molar ratio of the compound shown in formula II to the acid is 1:0.8-2; The methylating agent mentioned in step (3) is trimethyl orthoformate, and the temperature for adding the methylating agent and the reaction is 30-90℃.

2. The method as described in claim 1, characterized in that, The methylating agent is added in batches.

3. The method as described in claim 2, characterized in that, The methylation reagent is added dropwise to each batch.

4. The method as described in claim 1, characterized in that, The molar ratio of the compound shown in Formula II to the acid is 1:1.1 to 1:1.

5.

5. The method as described in claim 1, characterized in that, The molar ratio of the compound shown in Formula II to the methylating agent is 1:1-10.

6. The method as described in claim 5, characterized in that, The molar ratio of the compound shown in Formula II to the methylating agent is 1:

8.

7. The method as described in claim 1, characterized in that, The addition of the methylating agent and the reaction temperature in step (3) are 45-80℃.

8. The method as described in claim 1, characterized in that, The post-processing described in step (4) includes (4a): cooling the reaction system obtained in step (3), adjusting the pH to alkaline, and separating the insoluble matter.

9. The method as described in claim 8, characterized in that, Step (4) further includes (4b): allowing the liquid obtained after separating the insoluble matter in step (4a) to stand, extracting the aqueous layer with an organic solvent, and washing and concentrating the extract to obtain the crude product.

10. The method as described in claim 9, characterized in that, In step (4b), the organic solvent used for extraction is ethyl acetate.

11. The method as described in claim 9, characterized in that, Step (4) also includes a purification step: the crude product obtained in step (4b) is pulped in an organic solvent.

12. The method as described in claim 11, characterized in that, In the purification step, the organic solvent is a non-polar solvent.

13. The method as described in claim 11, characterized in that, In the purification step, the organic solvent is toluene.

14. A method for preparing a compound of Formula III, comprising the steps of the method according to any one of claims 1-13, and further comprising the step of nitro-reducing the compound of Formula I. 。 15. A method for preparing a compound of formula IV or a salt thereof, comprising the steps of the method of claim 14, and further comprising the step of reacting the compound of formula V with the compound of formula III. in, Y represents a halogen; n is an integer from 1 to 5; R1 and R2 are each independently C1-C6 alkyl groups.

16. The method as described in claim 15, characterized in that, The compound shown in Formula IV has the following structure: 。

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