A method for preparing a key intermediate of finerenone

Abstract

The invention provides a method for preparing a key intermediate of finerenone with high chiral purity, and uses D-camphorsulfonic acid and an organic solvent as a chemical resolution system to prepare 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate, with an ee value of up to 98.0%. The preparation method provided by the invention has mild reaction conditions, simple process, high reaction yield, low production cost, and is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis, and specifically relates to a method for preparing a finerenone intermediate 2-cyanoethyl-(4S)-4-(4-cyano-2-methoxyphenyl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate. Background of the Invention

[0002] Finerenone is a non-steroidal selective mineralocorticoid receptor antagonist developed by Bayer. It was first approved by the US FDA in July 2021 for the treatment of adult patients with chronic kidney disease and type 2 diabetes. Finerenone's chemical name is (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxamide, and its structural formula is as follows:

[0003]

[0004] Among them, CN101641352B and CN107849043B both disclose methods for preparing finerenone, using cyanoethyl acetoacetate and acetoacetamide as raw materials to obtain finerenone through different synthetic routes. The defects of these preparation methods are that finerenone racemate is separated after being prepared. Although the preparation of S-configuration finerenone by chiral phase HPLC separation or SMB equipment chromatographic separation method can provide higher optical purity, the total yield is low. Especially under GMP conditions, the equipment purchase cost is high, the amount of mobile phase solvent used is large, the operation is difficult, and continuous production cannot be ensured, which is not suitable for industrial production.

[0005] In addition, in order to find a method for preparing finerenone with higher optical purity and at the same time to reduce production costs so that it can be produced in conventional pilot plant equipment (stirring tank / separation device) of traditional pharmaceutical factories, CN114667284A first mentioned the use of a chemical splitting method to prepare finerenone. The application further discloses a method for preparing finerenone intermediate 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate and a finished product by using (2R,3R)-2,3-di(4-nitrobenzoyl)tartaric acid as a splitting agent, as shown in Scheme 1:

[0006]

[0007] This route uses (2R,3R)-2,3-di(4-nitrobenzoyl)tartaric acid and 2-cyanoethyl 4-(4-cyano-2-methoxyphenyl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (compound of formula IV) to separate into salts. The ee value of the first diastereomeric salt obtained is only 85% at most. After further purification, the ee value is increased to 98%. The total yield of the two steps is only 38.8%. In addition, the separation reagent (2R,3R)-2,3-di(4-nitrobenzoyl)tartaric acid is expensive and difficult to obtain.

[0008] In addition, the route also mentions the attempt to use other types of splitting agents, such as (S)-(+)-mandelic acid, L-glutamic acid, L-lactic acid, malic acid and other dozen commonly used chiral splitting agents to react with racemic compound IV in conventional organic solvents. However, no salt formation was observed in any case; on the contrary, the racemate precipitated from the solvent without forming a salt, so the above chemical splitting experiments all ended in failure. The inventor of this route measured the pKa (for base) of compound IV as 4.3, and inferred from this that conventional optical splitting by forming diastereomeric salts with organic acids should be impossible. According to the conclusion of route 1, only the unique (2R, 3R)-2,3-di(4-nitrobenzoyl)tartaric acid splitting agent can be used to split compound IV. The applicant holds a different view on this. The applicant believes that the chemical resolution effect of the compound of formula IV depends on multiple factors, such as: the type and amount of the resolution agent, the type and amount of the organic solvent, the crystallization time, the crystallization temperature, the post-treatment method, etc. If the conclusion of whether the organic acid and base can form a salt is simply inferred by the pKa size of the compound of formula IV, it may be too arbitrary. The conclusion of route 1 may be wrong, one-sided, and flawed. The applicant boldly predicts that in addition to the (2R, 3R)-2,3-di(4-nitrobenzoyl)tartaric acid resolution agent, there should be other organic acid resolution agents that can successfully implement the resolution of the compound of formula IV.

[0009] In summary, there is an urgent need to develop a method for preparing S-configuration finerenone that is suitable for industrial production and has good resolution effect, high reaction yield and reliable quality control. At the same time, it can also further verify that the conclusions and assumptions of the above route 1 are untenable. Summary of the invention

[0010] The invention provides a method for preparing a key intermediate of finerenone, 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate and finerenone thereof. The preparation method has high optical purity, mild reaction conditions, simple process, high reaction yield, low production cost and is suitable for industrial production.

[0011] Specifically, the present invention provides a method for preparing 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate, a key intermediate of finerenone, which comprises the following steps:

[0012]

[0013] The applicant unexpectedly discovered that the resolving system using D-camphorsulfonic acid and an organic solvent can also successfully resolve the compound of formula II by optimizing the resolving conditions (e.g., the type and amount of the resolving agent, the type and amount of the organic solvent, the crystallization time, the crystallization temperature, the post-treatment method, etc.), and achieved significant progress or unexpected technical effects. The specific implementation plan is as follows:

[0014] Wherein step 1) using the compound of formula II as a raw material, sequentially adding D-camphorsulfonic acid and an organic solvent, heating for reaction, cooling and crystallizing after the reaction, filtering, and drying to obtain a compound of formula IV;

[0015] In step 2), the compound of formula IV is added to an organic solvent, treated with a base under cooling conditions, filtered, and dried to obtain a compound of formula I.

[0016] The organic solvent used in step 1) is one or more of an alcohol solvent, an ether solvent, a ketone solvent, a halogenated hydrocarbon solvent, and a nitrile solvent,

[0017] The alcohol solvent is selected from one or more of methanol, ethylene glycol, and n-propanol, and methanol is more preferred.

[0018] The ether solvent is selected from tetrahydrofuran,

[0019] The ketone solvent is selected from acetone,

[0020] The halogenated hydrocarbon solvent is selected from one or more of dichloromethane, chloroform and 1,2-dichloroethane, and more preferably one or more of dichloromethane and chloroform.

[0021] The nitrile solvent is selected from acetonitrile.

[0022] The molar ratio of the compound of formula II used in step 1) to D-camphorsulfonic acid is 1:(0.5-2), preferably 1:(0.8-1.2).

[0023] The reaction temperature in step 1) is room temperature-solvent reflux reaction and the reaction time is 0.5-5 hours.

[0024] The cooling crystallization temperature in step 1) is 10-40°C, preferably 10-20°C.

[0025] The organic solvent used in step 2) is a mixed solvent of alcohol / water, wherein the volume ratio of alcohol to water is 1:(2-10), preferably methanol / water, ethanol / water, isopropanol / water, the volume ratio of alcohol to water is 1:(2-8), more preferably methanol / water, ethanol / water, the volume ratio of alcohol to water is 1:(2-4),

[0026] The base used in step 2) is selected from an organic base and an inorganic base. The organic base is further preferably one or more of triethylamine and pyridine. The inorganic base is further preferably one or more of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and sodium phosphate. Sodium phosphate is more preferred. The molar ratio of the compound of formula IV to the base is 1:(1-2).

[0027] The alkali treatment reaction temperature in step 2) is 0-10° C., more preferably 0-5° C. The reaction time is 10 minutes to 2 hours.

[0028] Beneficial Effects

[0029] 1. Although (2R,3R)-2,3-di(4-nitrobenzoyl)tartaric acid is used as a splitting agent in Route 1, and it is concluded that only (2R,3R)-2,3-di(4-nitrobenzoyl)tartaric acid can be successfully split. The applicant puts forward a different viewpoint. On the premise that Route 1 gives a negative conclusion, it is first proposed that the splitting system using D-camphorsulfonic acid and an organic solvent can also successfully split the compound of Formula IV and achieve a significant splitting effect, which has the potential of best-in-class.

[0030] 2. The technical solution implemented by this application can not only break the technical monopoly and blockade of Route 1, but also have independent intellectual property rights.

[0031] 3. The present application uses D-camphorsulfonic acid and acetonitrile, tetrahydrofuran, acetone, chloroform, and dichloromethane for splitting. Since the yield and optical purity of the intermediate compound of formula I are effectively controlled, the intermediate is used to continue to synthesize subsequent finerenone, which has an optical purity of up to 100.0% and a single impurity of less than 0.10%, which meets the quality standard requirements of the raw material drug and lays a solid foundation for the quality of subsequent preparation products. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 HPLC spectrum of isomers of the raw material formula II compound

[0033] Figure 2 HPLC chromatogram of isomers of compound IV (methanol as solvent) in Example 1

[0034] Figure 3 HPLC chromatogram of isomers of compound IV (methanol / water V:V=3:1 as solvent) in Example 1

[0035] Figure 4 HPLC chromatogram of isomers of compound IV (ethanol as solvent) in Example 1

[0036] Figure 5 HPLC Spectrum of Isomers of Compound IV in Example 1 (Isopropyl Acetate as Solvent)

[0037] Figure 6 HPLC chromatogram of isomers of compound IV (ethyl acetate as solvent) in Example 1

[0038] Figure 7 HPLC Spectrum of Isomers of Compound IV in Example 1 (Acetonitrile as Solvent)

[0039] Figure 8 HPLC Spectrum of Isomers of Compound IV (TEF as Solvent) in Example 1

[0040] Fig. 9 HPLC Spectrum of Isomers of Compound IV in Example 1 (Acetone as Solvent)

[0041] Fig.10 HPLC chromatogram of isomers of compound IV (chloroform as solvent) in Example 1

[0042] Fig.11 HPLC chromatogram of isomers of compound IV in Example 1 (dichloromethane as solvent)

[0043] Fig.12 HPLC Spectrum of Related Substances of Finerenone in Example 4

[0044] Fig.13 HPLC Spectrum of Isomers of Finerenone in Example 4

[0045] Fig.14 Example 1 Compound of Formula IV 1 HNMR spectrum

[0046] Fig.15 Example 4: 1 HNMR spectrum

[0047] Fig.16 Example 4: 13 CNMR spectrum DETAILED DESCRIPTION

[0048] Example 1 - Preparation of Compound IV, Methanol as Solvent

[0049] In a 250ml reaction bottle, add 2-cyanoethyl 4-(4-cyano-2-methoxyphenyl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (5.0g, 12.4mmol), D-camphorsulfonic acid (3.0g, 13mmol), methanol (100ml), heat to reflux and stir to react for 2 hours. After the reaction is completed, slowly cool to 10-20℃ and stir to crystallize for 1 hour, filter to dry, and dry the filter cake with hot air at 50℃ to obtain 3.55g solid, with a yield of 45.1% and an ee value of 85.1%. 1 HNMR (400MHz, [D6]-DMSO): δ=0.75(s,3H), 1.04(s,3H), 1.26~1.36(m,2H), 1.80~1.88(m ,2H), 1.96(t,1H,J=4.3Hz), 2.11(s,3H), 2.22~2.29(m,1H), 2.38(s,3H), 2.47(d,1H,J= 14.8Hz), 2.59~2.67(m,1H), 2.76~2.81(m,2H), 2.94(d,1H,J=14.7Hz), 3.75(s,3H), 4.0 6(m,2H), 5.27(s,1H), 7.19(s,1H), 7.26(m,1H), 7.35(m,2H), 8.47(s,1H), 11.53(s,1H).

[0050] According to the content of Example 1, we investigated the separation effect of using D-camphorsulfonic acid and the compound of formula II to form salts in different solvents, see Table 1.

[0051] Table 1

[0052]

[0053] The above results and the characterization results of the H NMR spectrum data of the prepared compound of formula IV indicate that the compound of formula II can be salted with D-camphorsulfonic acid in a ratio of 1:1. The resolution effect of the salt formation of the compound of formula II with D-camphorsulfonic acid is not only related to the solubility of the two diastereoisomer salts generated by the reaction in the solvent, but may also be related to the solubility of the raw material compound of formula II in the solvent.

[0054] Through experiments, we found that the solubility of the compound of formula II in ethanol, ethyl acetate, and isopropyl acetate is slightly soluble or almost insoluble. During the reaction, it may not participate in the salt-forming reaction due to poor solubility, and thus precipitate as a racemate, so almost no separation effect is observed. There is a certain separation effect in solvents such as methanol and methanol / water; it is particularly surprising that there is a very high separation effect in tetrahydrofuran, acetone, chloroform, dichloromethane, and acetonitrile. The ee value of the first diastereomeric salt of the compound of formula IV can reach up to 98.0%, and the yield is 42-45%, which is significantly better than the ee value of the first diastereomeric salt obtained by the existing separation technology. The highest value is only 85%, and the ee value is increased to 98% after further purification, and the two-step yield is only 38.8%.

[0055] Example 2—Using D-(+)-dibenzoyltartaric acid as a resolving agent,

[0056] According to the content of Example 1, we investigated the resolution effect of using D-(+)-dibenzoyltartaric acid and the compound of formula II to form a salt in dichloromethane, see Table 2.

[0057] Table 2

[0058]

[0059] No salt formation was observed.

[0060] Example 3 - Preparation of Compounds of Formula I

[0061] In a 1L reaction bottle, add the compound of formula IV (30.5 g, 48 mmol) and ethanol / water mixed solvent (300 ml, volume ratio of 1:3), stir, cool to 0-5°C, slowly add 20% sodium phosphate aqueous solution, adjust pH to 7-8, stir for 10-20 minutes after adjustment, filter to dryness, and dry the filter cake with hot air at 50°C to obtain 17.5 g of solid with a yield of 90.3%.

[0062] Example 4 - Preparation of Finerenone

[0063] After preparing the compound of formula I, we further react it with triethyl orthoacetate to obtain compound V, then hydrolyze it to obtain compound VI, then condense it with CDI, react it with ammonia water, and finally purify it with ethanol to obtain finerenone, with an optical purity of up to 100.0%, and a single impurity of less than 0.10%, which meets the quality standard requirements of raw materials. The reaction formula is as follows:

[0064]

[0065] Preparation of compounds of formula V

[0066] In a 250ml reaction bottle, add the compound of formula I (17.0g, 42mmol), triethyl orthoacetate (17.1g, 105mmol), NMP (25.5g), stir, add concentrated sulfuric acid (1.2g) dropwise at room temperature, and after the addition is complete, heat to 100-110°C and react for 3 hours. After the reaction is complete, cool to 45-50°C and add water (25ml), after the addition is complete, stir for about 10 minutes, solid gradually precipitates, then continue to add water (35ml) at this temperature, after the addition is complete, slowly cool to 0-5°C and stir for crystallization for 2 hours, filter to dry, and dry the filter cake at 50°C with hot air to obtain 16.5g of solid, with a yield of 90.8%.

[0067] Preparation of compounds of formula VI

[0068] In a 500ml reaction bottle, add the compound of formula V (16.0g, 37mmol), THF (90ml), water (20ml), stir, cool to 0-5℃, add 1N sodium hydroxide aqueous solution (74ml, 74mmol), and continue to react at this temperature for 2 hours. After the reaction is completed, wash twice with methyl tert-butyl ether (35ml×2), place the aqueous phase in a 500ml reaction bottle, cool to 0-5℃, slowly add 2N dilute hydrochloric acid to adjust pH=5-6, continue to stir and crystallize for 1 hour, filter, rinse with appropriate amount of water, dry, and dry the filter cake at 40℃ under reduced pressure to obtain 12.4g of solid, with a yield of 88.3%.

[0069] Preparation of finerenone

[0070] In a 250ml reaction bottle, add the compound of formula VI (10.0g, 26mmol), THF (100ml), CDI (5.6g, 35mmol), and stir the reaction at room temperature overnight. After the reaction is completed, add 25% ammonia water (40ml), heat to reflux and stir the reaction for 1 hour. After the reaction is completed, add 100ml of water, stir and crystallize at room temperature for 2 hours, filter, rinse with appropriate amount of water, dry, and dry the filter cake with hot air at 50℃ to obtain 9.2g of crude solid, with a yield of 92.2%.

[0071] Recrystallization process

[0072] In a 250ml reaction bottle, add the above crude product (9.0g) and ethanol (180ml), heat to reflux and stir to dissolve. After the solution is clear, filter it hot, place the filtrate in a 45℃ water bath and evaporate it until about 50ml of solution remains. At this time, solid has precipitated, then slowly cool it to room temperature and stir to crystallize for 6 hours, filter it to dryness, and dry the filter cake with hot air at 50℃ to obtain 8.2g of finished solid, with a yield of 91.1% and an ee value of 100.0%.

[0073] 1HNMR (400MHz, [D6]-DMSO): δ = 1.05 (t, 3H, J = 7.0Hz), 2.13 (s, 3H), 2.19 (s, 3H), 3.83 (s, 3H), 3.98 ~ 4.08 (m, 2H), 5 .38(s,1H), 6.70~6.77(m,1H), 7.15(d,1H,J=7.8Hz), 7.27~7.30(m,1H), 7.38(m,1H), 7.56(s,1H), 7.69(s,1H).

[0074] 13 CNMR (100MHz, [D6]-DMSO): δ=14.2, 14.7, 18.5, 32.9, 56.5, 61.0, 103.6, 105.8, 110.0 ,111.9,114.6,119.4,125.2,131.3,138.5,142.1,144.6,144.7,156.1,159.8,170.1.

[0075] It should be pointed out that the above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with the technology to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing a key intermediate of finerenone, characterized in that: The steps include: (1) using the compound of formula II as a raw material, adding D-camphorsulfonic acid and an organic solvent in sequence, heating for reaction, cooling and crystallizing after the reaction, filtering, and drying to obtain the compound of formula IV; (2) adding the compound of formula IV to an organic solvent, treating with a base under cooling conditions, filtering, and drying to obtain a compound of formula I; Wherein step 1) is one or more of alcohol solvent, ether solvent, ketone solvent, halogenated hydrocarbon solvent and nitrile solvent; The alcohol solvent is selected from methanol; The ether solvent is selected from tetrahydrofuran; The ketone solvent is selected from acetone; The halogenated hydrocarbon solvent is selected from dichloromethane and chloroform; The nitrile solvent is selected from acetonitrile; The reaction temperature in step 1) is room temperature-solvent reflux reaction, and the reaction time is 0.5-5 hours; the molar ratio of the compound of formula II used in step 1) to D-camphorsulfonic acid is 1:(0.8-1.2); The cooling crystallization temperature in step 1) is 10-20°C.

2. The method for preparing a key intermediate of finerenone according to claim 1, characterized in that: The base used in step 2) is one or more of triethylamine, pyridine, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, and sodium phosphate, and the molar ratio of the compound of formula IV to the base is 1:(1-2).

3. The method for preparing a key intermediate of finerenone according to claim 2, characterized in that: The base used in step 2) is sodium phosphate.

4. The method for preparing a key intermediate of finerenone according to claim 1, characterized in that: The alkali treatment reaction temperature in step 2) is 0-5°C, and the reaction time is 10 minutes to 2 hours.

Images