Fnerenone intermediate as well as preparation method and application thereof

Abstract

The invention discloses a fenerenone intermediate II with a brand new structure or an optical isomer IIa of the fenerenone intermediate II and a preparation method of the fenerenone intermediate II, compared with a reaction taking 3-oxobutyric acid-2-cyanoethyl ester as a starting material, the reaction yield is improved; the invention further discloses a fenerenone intermediate III with a brand new structure or an optical isomer IIIa thereof and a preparation method thereof. The fenerenone intermediate III or the optical isomer IIIa has ester bond reduction reaction activity. Besides, the invention further discloses application of the Fnerenone intermediate II or the optical isomer IIa thereof and the intermediate III or the optical isomer IIIa thereof in preparation of Fnerenone, reduction can be achieved under the action of reducing agents such as zinc powder, expensive catalysts such as palladium carbon are not needed, the technical effect of rapid reaction under mild reaction conditions is achieved, and the method is not only suitable for small-scale tests, but also suitable for industrial production. The method is more suitable for industrial large-scale production.

Description

Technical Field

[0001] The invention belongs to the technical field of finerenone synthesis methods, and specifically relates to a finerenone intermediate and a preparation method and application thereof. Background Art

[0002] Finerenone (English name: Finerenone, chemical name: (4s)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide, structural formula as follows) is a non-steroidal selective mineralocorticoid receptor antagonist developed by Bayer. It blocks mineralocorticoid receptor-mediated sodium reabsorption and excessive activation of mineralocorticoid receptors in epithelial (such as kidneys) and non-epithelial (such as heart and blood vessels) tissues, and can be used to prevent and / or treat cardiovascular and renal diseases such as heart failure and diabetic nephropathy.

[0003]

[0004] The original compound patent CN101641352A discloses a method for preparing phenarenin, and the synthesis route is as follows. However, the synthesis route has the following technical problems: the yield of preparing intermediate 1 by reacting starting material 1 (2-methoxy-4-cyanobenzaldehyde), starting material 2 (3-oxobutyric acid-2-cyanoethyl ester), and starting material 3 (4-amino-5-methylpyridin-2(1H)-one) is only 48%, and the yield of intermediate 2 is only 48%×76%=36% (see Examples 24A and 25A), thereby affecting the product yield.

[0005]

[0006] Patent CN 114605410 A discloses a method for preparing finerenone, and the synthetic route is as follows. In Example 1, the effect of different acetoacetic acid lipids as starting material 2 analogs on the yield of intermediate 1 analogs was investigated, wherein when starting material 2 analogs were 3-oxobutyric acid-2-benzyl ester, the yield of intermediate 1 analogs was the highest at 91%, and the yield of intermediate 2 analogs was 91%×92%=84% (see Example 1).

[0007]

[0008] Therefore, whether there are other analogs of starting material 2 that can improve the yield of intermediate 2 analogs remains to be studied.

[0009] The reaction characteristics of intermediate 3 analogs obtained by reacting different starting material 2 analogs are different, resulting in significant differences in the reaction conditions for preparing intermediate 5 and the yield of intermediate 5 obtained.

[0010] Patents CN101641352A, CN114667284A, and CN114698375A all disclose intermediate 3 The ester bond is hydrolyzed under alkaline conditions using sodium hydroxide; Patent CN114605410A discloses intermediate 3 analogs The ester bond was hydrolyzed under alkaline conditions using potassium trimethylsilanol. However, alkaline hydrolysis is not suitable for other intermediate 3 analogs, which may increase the risk of aromatization impurities and reduce the yield of intermediate 5.

[0011] Intermediate 3 analogues disclosed in patent CN115340539A The palladium-carbon catalytic reduction of ester bonds has low ester bond reduction reaction activity, and expensive catalysts are required to increase production costs.

[0012] In summary, how to optimize the starting material 2 analog to prepare finerenone intermediate 2 analog and intermediate 3 analog, which can not only improve the yield of intermediate 2 analog, but also make the intermediate 3 analog have high ester bond reduction reaction activity, is a technical problem that has not been solved in the art. Summary of the invention

[0013] The technical problem to be solved by the present invention is to provide a phenarenic acid intermediate II or III prepared from an analog of starting material 2, which can not only improve the yield of intermediate II; but also the intermediate III has high ester bond reduction reaction activity, and intermediate 5 can be prepared without expensive catalysts.

[0014] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0015] On the one hand, the present invention provides a novel finerenone intermediate, which is a compound shown in formula II or its optical isomer IIa: Where R0 is halogenated C 1-4 alkyl.

[0016] Preferably, in intermediate II or intermediate IIa, R0 is C substituted with three halogen atoms. 1-4 Alkyl groups include, but are not limited to, one of -CCl3, -CH2CCl3, -CH2CH2CCl3, -CH(CH3)2CCl3, -CF3, -CH2CF3, -CH2CH2CF3, and -CH2CBr3.

[0017] More preferably, in intermediate II or intermediate IIa, R0 is trichlorosubstituted C 1-4 Alkyl groups include, but are not limited to, -CCl3, -CH2CCl3, -CH2CH2CCl3, and -CH(CH3)2CCl3.

[0018] Most preferably, in intermediate II or intermediate IIa, R0 is -CH2CCl3.

[0019] The present invention also provides a method for preparing the aforementioned finerenone intermediate, comprising the following reaction route:

[0020]

[0021] Preferably, in the step of preparing intermediate I from raw materials, the raw materials 2-methoxy-4-cyanobenzaldehyde and acetoacetate are dissolved in a reaction solvent, and intermediate I is obtained by catalytic reaction under the action of a catalyst.

[0022] Those skilled in the art can understand that the intermediate I is prepared by Knoevenagel condensation reaction conditions, and the reaction solvent includes but is not limited to one or more of methanol, ethanol, isopropanol, tert-butanol, tri-amyl alcohol, n-butanol, 2-butanol, dichloromethane, ethyl acetate, isopropyl acetate, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone; the catalyst includes but is not limited to one or more of glacial acetic acid, hexanoic acid, piperidine, quinoline, methylamine, dimethylamine, ethylamine, and diethylamine.

[0023] More preferably, 2-methoxy-4-cyanobenzaldehyde and acetoacetate are dissolved in isopropanol and reacted under the catalysis of piperidine and acetic acid to obtain intermediate I.

[0024] More preferably, the amount of isopropanol used is 2 to 30 times the mass of 2-methoxy-4-cyanobenzaldehyde.

[0025] Most preferably, the amount of isopropanol used is 4 to 6 times the mass of 2-methoxy-4-cyanobenzaldehyde.

[0026] More preferably, the molar ratio of 2-methoxy-4-cyanobenzaldehyde to acetoacetate is 1:(1-2).

[0027] Most preferably, the molar ratio of 2-methoxy-4-cyanobenzaldehyde to acetoacetate is 1:(1.05-1.2).

[0028] More preferably, the molar ratio of piperidine, glacial acetic acid and 2-methoxy-4-cyanobenzaldehyde is (0.01-0.3):(0.01-0.3):1.

[0029] Most preferably, the molar ratio of piperidine, glacial acetic acid and 2-methoxy-4-cyanobenzaldehyde is (0.05-0.15):(0.05-0.15):1.

[0030] More preferably, the reaction temperature is 0 to 100°C.

[0031] Most preferably, the reaction temperature is 20-40°C.

[0032] Preferably, in the step of preparing intermediate II from intermediate I, intermediate I and 4-amino-5-methylpyridin-2(1H)-one are dissolved in a reaction solvent, and condensation reaction is carried out to obtain intermediate II.

[0033] Those skilled in the art will appreciate that intermediate II is prepared by carbonyl-amine condensation reaction conditions, and the reaction solvent includes but is not limited to one or more of methanol, ethanol, isopropanol, tert-butanol, tri-amyl alcohol, n-butanol, 2-butanol, dichloromethane, ethyl acetate, isopropyl acetate, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone.

[0034] More preferably, intermediate I and 4-amino-5-methylpyridin-2(1H)-one are dissolved in isopropanol and reacted to obtain intermediate II.

[0035] More preferably, the amount of isopropanol used is 2 to 50 times the mass of the intermediate I.

[0036] Most preferably, the amount of isopropanol used is 8 to 10 times the mass of the intermediate I.

[0037] More preferably, the molar ratio of intermediate I to 4-amino-5-methylpyridin-2(1H)-one is (0.9-1.5):1.

[0038] Most preferably, the molar ratio of intermediate I to 4-amino-5-methylpyridin-2(1H)-one is (0.95-1.05):1.

[0039] On the other hand, the present invention provides a novel finerenone intermediate, which is a compound shown in formula III or its optical isomer IIIa: Where R0 is halogenated C 1-4 alkyl.

[0040] Preferably, in intermediate III or intermediate IIIa, R0 is C substituted with three halogen atoms. 1-4 Alkyl groups include, but are not limited to, one of -CCl3, -CH2CCl3, -CH2CH2CCl3, -CH(CH3)2CCl3, -CF3, -CH2CF3, -CH2CH2CF3, and -CH2CBr3.

[0041] More preferably, in intermediate III or intermediate IIIa, R0 is trichlorosubstituted C 1-4 Alkyl groups include, but are not limited to, -CCl3, -CH2CCl3, -CH2CH2CCl3, and -CH(CH3)2CCl3.

[0042] Most preferably, in intermediate III or intermediate IIIa, R0 is -CH2CCl3.

[0043] The present invention also provides a method for preparing the aforementioned finerenone intermediate, comprising the following reaction route:

[0044]

[0045] Preferably, intermediate II or its optical isomer IIa and triethyl orthoacetate are dissolved in a reaction solvent and subjected to an alkylation reaction in the presence of a catalyst to obtain intermediate III or its optical isomer IIIa.

[0046] Those skilled in the art can understand that intermediate III is prepared by alkylation reaction conditions, and the reaction solvent includes but is not limited to one or more of ethyl acetate, isopropyl acetate, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone; the catalyst includes but is not limited to one or more of toluenesulfonic acid, benzenesulfonic acid, concentrated sulfuric acid, methanesulfonic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid.

[0047] More preferably, intermediate II or its optical isomer IIIa and triethyl orthoacetate are dissolved in N-methylpyrrolidone and reacted under the catalysis of sulfuric acid to obtain intermediate III or its optical isomer.

[0048] More preferably, the amount of N-methylpyrrolidone used is 0.5 to 30 times the mass of intermediate II.

[0049] Most preferably, the amount of N-methylpyrrolidone used is 8 to 10 times the mass of intermediate II.

[0050] More preferably, the molar ratio of intermediate II or its optical isomer to triethyl orthoacetate is 1-10.

[0051] Most preferably, the molar ratio of intermediate II or its optical isomer to triethyl orthoacetate is 4-6.

[0052] More preferably, the molar ratio of sulfuric acid to intermediate II or its optical isomer is (0.1-1):1.

[0053] Most preferably, the molar ratio of sulfuric acid to intermediate II or its optical isomers is 0.5:1.

[0054] More preferably, the reaction temperature is 50-150°C.

[0055] Most preferably, the reaction temperature is 100-120°C.

[0056] In another aspect, the present invention further provides a use of the above-mentioned finerenone intermediate (including but not limited to compounds represented by formula II, formula IIa, formula III, and formula IIIa) in the preparation of finerenone.

[0057] Preferably, the intermediate III or intermediate IIIa is subjected to a reduction reaction to obtain intermediate 5 or its optical isomer 5a:

[0058]

[0059] More preferably, the reduction reaction solvent includes, but is not limited to, one or more of tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, acetone, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone.

[0060] Most preferably, the reduction reaction solvent is dimethyl sulfoxide.

[0061] More preferably, the amount of the reduction reaction solvent is 2 to 30 times the mass of the intermediate III or its optical isomers.

[0062] Most preferably, the amount of the reduction reaction solvent is 5 times the mass of the intermediate III or its optical isomers.

[0063] More preferably, the reducing agent for the reduction reaction is zinc powder and glacial acetic acid.

[0064] More preferably, the molar ratio of zinc powder, glacial acetic acid and intermediate III or its optical isomer is (0.5-20):(0.5-20):1.

[0065] Most preferably, the molar ratio of zinc powder, glacial acetic acid and intermediate III or its optical isomer is 2-6:1-2:1.

[0066] More preferably, the reduction reaction temperature is 0 to 80° C., and the reaction time is 0.5 h to 24 h.

[0067] Most preferably, the reduction reaction temperature is 20-30°C and the reaction time is 0.5h-1h.

[0068] In addition, the present invention also provides a method for preparing finerenone, comprising the following steps:

[0069]

[0070] Preferably, in the aforementioned route for preparing finerenone, any step, whether in the step of preparing intermediate III from intermediate II, or in the step of preparing intermediate 5 from intermediate III, or in the step of preparing finerenone from intermediate 5, can be chirally resolved.

[0071] More preferably, in the aforementioned route for preparing finerenone, chiral resolution is performed in the step of preparing intermediate 5 from intermediate III, comprising the following steps:

[0072]

[0073] The above chiral separation method has the following specific steps:

[0074]

[0075] Compared with the prior art, the present invention has the following beneficial effects:

[0076] ① The preferred starting material 2 of this application is (wherein R0 is a halogenated C 1-4 alkyl), and the intermediate II is obtained by reaction. Compared with CN101641352A which uses 3-oxobutyric acid-2-cyanoethyl ester as the starting material 2, the reaction yield is improved.

[0077] ②This application uses starting material 2 as (Wherein, R0 is a halogenated C 1-4 The intermediate III or its optical isomer IIIa obtained by the reaction is not suitable for preparing the intermediate 5 or its optical isomer 5a under alkaline hydrolysis conditions, and a large amount of aromatization impurities are easily produced;

[0078] However, studies have found that intermediate III or its optical isomer IIIa has ester bond reduction reaction activity, especially intermediate III or IIIa where R0 is -CH2CCl3, which can be reduced under the action of reducing agents such as zinc powder, without the need for expensive catalysts such as palladium carbon, and can achieve a rapid reaction effect under mild reaction conditions, making it suitable for large-scale production.

[0079] BRIEF DESCRIPTION OF THE DRAWINGS

[0080] Figure 1 This is the chiral purity spectrum of intermediate IV before resolution in Example 4;

[0081] Figure 2 This is the chiral purity spectrum of intermediate IV after resolution in Example 4. DETAILED DESCRIPTION

[0082] The technical solution of the present invention is further described below in conjunction with the accompanying drawings and embodiments. However, the protection scope of the present invention includes but is not limited to these embodiments, and any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the protection scope of the present invention.

[0083] The instruments and reagents used in the examples and comparative examples of the present invention are all commercially available products. As examples, the models and manufacturer information of some reagents are as follows:

[0084] 2-Methoxy-4-cyanobenzaldehyde (Manufacturer: Keju Biotechnology);

[0085] 2,2,2-trichloroethyl 3-oxobutyrate (homemade);

[0086] 4-amino-5-methylpyridin-2(1H)-one (manufacturer: Keju Biotechnology);

[0087] Triethyl orthoacetate (manufacturer: Shanghai MacLean);

[0088] D-(+)-Di-p-toluoyltartaric acid (manufacturer: Shanghai McLean).

[0089] Example 1 Preparation of Intermediate II

[0090]

[0091] Add 2-methoxy-4-cyanobenzaldehyde (100.0 g, 620.5 mmol), 550 ml of isopropanol, piperidine (5.30 g, 62.05 mmol) and glacial acetic acid (3.75 g, 62.05 mmol) into a reaction flask, add dropwise 50 ml of isopropanol solution of 2,2,2-trichloroethyl 3-oxobutyrate (159.4 g, 682.6 mmol), stir at 20-30°C for 1-3 h, cool to 0-5°C, stir and crystallize, filter, wash the filter cake with isopropanol, and dry to obtain light yellow solid intermediate I (201.44 g, 534.9 mmol) with a yield of 86.2%.

[0092] Characterization of Intermediate I: 1 H NMR (400MHz, CDCl3): δ7.93(1H), δ7.53(1H), δ7.29(1H), δ7.18(1H), δ4.82(2H), δ3.96(3H), δ2.53(3H).

[0093] Add intermediate I (200.0 g, 531.1 mmol), 1600 ml of isopropanol and 4-amino-5-methylpyridin-2(1H)-one (62.63 g, 504.5 mmol) into a reaction flask, heat to 80-90°C, reflux with stirring for 6-18 h, cool to 0-5°C for crystallization, filter, wash the filter cake with isopropanol, and dry to obtain intermediate II (205.42 g, 425.5 mmol) with a yield of 80.1%.

[0094] Intermediate II Characterization: 1H NMR (400MHz, CDCl3): δ10.59(1H), δ7.59(1H), δ7.16(1H), δ7.02(1H), δ6.84(1H), δ5.96(1H), δ5.43(1H), δ4.76(1H), δ4.63(1H), δ3.74(3H), δ2.45(3H), δ2.05(3H).

[0095] Example 2 Preparation of Intermediate II

[0096]

[0097] Add 2-methoxy-4-cyanobenzaldehyde (15.0 g, 93.08 mmol), 68 ml of isopropanol, piperidine (0.80 g, 9.30 mmol) and glacial acetic acid (0.56 g, 9.30 mmol) into a reaction flask, add dropwise 7 ml of isopropanol solution of 2,2,2-trifluoroethyl 3-oxobutyrate (25.7 g, 139.59 mmol), stir and react at 20-30°C for 1-3 h, cool to 0-5°C, stir and crystallize, filter, wash the filter cake with isopropanol, and dry in vacuo to obtain light yellow solid intermediate I.

[0098] Add intermediate I, 270 ml of 2-butanol and 4-amino-5-methylpyridin-2(1H)-one (11.6 g, 88.43 mmol) into a reaction flask, heat to reflux and stir to react for 12 h, cool to 0-5 °C, stir and crystallize, filter, wash the filter cake with 2-butanol, and dry to obtain intermediate II (23.50 g, 54.22 mmol) with a total yield of 58.25%.

[0099] Example 3 Preparation of Intermediate III

[0100]

[0101] Add intermediate II (10 g, 20.72 mmol), 100 ml of N-methylpyrrolidone, triethyl orthoacetate (20 g, 123.3 mmol) and 1 g of concentrated sulfuric acid into a reaction flask, heat to 100-110°C for 1 h, cool to 0-10°C, add 50 ml of water, stir to crystallize, filter, wash the filter cake with water, and dry the filter cake to obtain a light yellow solid intermediate III (9.86 g, 19.30 mmol) with a yield of 93.2%.

[0102] Intermediate III Characterization: 1H NMR (400MHz, CDCl3): δ7.65(1H), δ7.48(1H), δ7.14(1H), δ7.00(1H), δ6.11(1H), δ5.48( 1H), δ4.78(1H), δ4.64(1H), δ4.15(2H), δ3.75(3H), δ2.49(3H), δ2.15(3H), δ1.22(3H).

[0103] Example 4 Preparation of Intermediate IIIa

[0104]

[0105] Add intermediate III (5.00 g, 9.79 mmol), 30 ml of ethanol / water (9:1) mixed solvent, and then add D-(+)-di-p-methylbenzoyltartaric acid (4.50 g, 11.65 mmol) into the reaction bottle, heat to 40-50°C for reaction for 1 h, cool to 0-10°C, stir and crystallize, filter, wash the filter cake with ethanol / water (9:1) mixed solvent, purify, and dry to obtain intermediate IV (3.6 g, 4.01 mmol) with a yield of 41.0%.

[0106] Figure 1 and Figure 2 It shows that after chemical resolution of D-(+)-di-p-toluoyltartaric acid, the enantiomeric purity (ee%) is 100%.

[0107] Add intermediate IV (10.00 g, 11.15 mmol) and 100 ml of ethanol / water (9:1) mixed solvent into a reaction flask, adjust the pH to 8.0-9.0 with 20% aqueous sodium hydroxide solution, cool to 0-5°C, stir and crystallize, filter, wash the filter cake with water, and dry to obtain intermediate IIIa (5.40 g, 10.57 mmol) with a yield of 94.8%.

[0108] Example 5 Preparation of Intermediate 5

[0109]

[0110] Add 60 ml of dimethyl sulfoxide, Zn (23.04 g, 352.39 mmol) and acetic acid (7.05 g, 117.46 mmol) into a reaction flask, add 90 ml of dimethyl sulfoxide solution of intermediate IIIa (30.0 g, 58.73 mmol) dropwise, react with stirring at 20-30°C for 0.5-1 h, filter, add water to the filtrate, stir and crystallize, filter, wash the filter cake with water, and dry to obtain intermediate 5 (18.0 g, 47.44 mmol) with a yield of 80.8%.

[0111] Example 6 Preparation of Intermediate 5

[0112]

[0113] Add 3 ml of tetrahydrofuran and intermediate IIIa (0.5 g, 1.084 mmol) to the reaction flask, cool down, and dropwise add 2 ml of tetrahydrofuran solution of potassium trimethylsilanol (0.278 g, 2.168 mmol). After addition, stir at 20-30°C for 5 h, filter, and wash the filter cake with tetrahydrofuran to obtain intermediate 5a. LC-MS shows a molecular weight of m / z 378 (M + +1), there is no intermediate 5a, and the obtained product is the aromatization of intermediate 5a.

Claims

1. A finerenone intermediate, which is a compound represented by formula II or its optical isomer IIa: in, R0 is halogenated C 1-4 alkyl.

2. The finerenone intermediate according to claim 1, characterized in that: In the intermediate II or intermediate IIa, R0 is C substituted with three halogen atoms. 1-4 Alkyl groups include, but are not limited to, one of -CCl3, -CH2CCl3, -CH2CH2CCl3, -CH(CH3)2CCl3, -CF3, -CH2CF3, -CH2CH2CF3, and -CH2CBr3.

3. The finerenone intermediate according to claim 2, characterized in that: In the intermediate II or intermediate IIa, R0 is a trichlorosubstituted C 1-4 Alkyl groups include, but are not limited to, -CCl3, -CH2CCl3, -CH2CH2CCl3, and -CH(CH3)2CCl3.

4. The finerenone intermediate according to claim 3, characterized in that: In the intermediate II or intermediate IIa, R0 is -CH2CCl3.

5. A method for preparing a finerenone intermediate according to any one of claims 1 to 4, characterized in that: The following reaction routes are included:

6. A finerenone intermediate, which is a compound represented by formula III or its optical isomer IIIa: in, R0 is halogenated C 1-4 alkyl.

7. The finerenone intermediate according to claim 6, characterized in that: In the intermediate III or intermediate IIIa, R0 is C substituted with three halogen atoms. 1-4 Alkyl groups include, but are not limited to, one of -CCl3, -CH2CCl3, -CH2CH2CCl3, -CH(CH3)2CCl3, -CF3, -CH2CF3, -CH2CH2CF3, and -CH2CBr3.

8. The finerenone intermediate according to claim 7, characterized in that: In the intermediate III or intermediate IIIa, R0 is trichlorosubstituted C 1-4 Alkyl groups include, but are not limited to, -CCl3, -CH2CCl3, -CH2CH2CCl3, and -CH(CH3)2CCl3.

9. The finerenone intermediate according to claim 8, characterized in that: In the intermediate III or intermediate IIIa, R0 is -CH2CCl3.

10. A method for preparing a finerenone intermediate according to any one of claims 6 to 9, characterized in that: The following reaction routes are included:

11. Use of the finerenone intermediate according to any one of claims 1 to 10 in the preparation of finerenone.

12. The use according to claim 11, characterized in that: The intermediate III or intermediate IIIa is subjected to reduction reaction to obtain intermediate 5 or its optical isomer 5a:

13. A method for preparing finerenone, characterized in that: The steps include:

14. The preparation method according to claim 13, characterized in that: In the step of preparing intermediate III from intermediate II, or in the step of preparing intermediate 5 from intermediate III, or in the step of preparing finerenone from intermediate 5, any step can be chiral resolved.

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