Preparation method of fenerenone

Abstract

The invention discloses a method for preparing fenerenone, which comprises the following steps of: (a) synthesizing a compound shown as a formula 3 by taking a compound shown as a formula 1 and a compound shown as a formula 2 as raw materials; (b) reducing the compound in the formula 3 under the action of a catalyst A and a catalyst B to obtain a compound in a formula 4; (c) synthesizing a compound shown in a formula 5 from the compound shown in the formula 4 and triethyl orthoformate under the catalysis of acid; (d) performing alkaline hydrolysis on the compound in the formula 5 to synthesize a compound in a formula 6; and (e) synthesizing the compound shown in the formula 6 into fenerenone shown in a formula 7 under the action of hexamethyldisilazane and CDI. According to the preparation method of the finerenone, chiral inversion is carried out from the intermediate, then the required chiral intermediate is obtained, then the finerenone is synthesized from the intermediate, splitting is carried out through the catalyst, half of chiral isomers cannot be lost, and the catalyst enables all raw materials to be converted into the required chiral configuration.

Description

Technical Field

[0001] The invention relates to a preparation method of finerenone, belonging to the technical field of pharmaceutical preparations. Background Art

[0002] Finerenone (BAY 94-8862) is a nonsteroidal selective mineralocorticoid receptor antagonist that has been shown in preclinical studies to block the deleterious effects of mineralocorticoid receptor overactivation. In patients with diabetes, mineralocorticoid receptor overactivation is thought to contribute to the progression of chronic kidney disease and cardiovascular impairment, which may be driven by metabolic, hemodynamic, or inflammatory and fibrotic factors.

[0003] The existing method for preparing finerenone has a relatively complicated synthesis process, and a large amount of finerenone is lost during the splitting process, resulting in a high production cost of finerenone. Summary of the invention

[0004] In view of the problems existing in the above-mentioned prior art, the present invention provides a method for preparing finerenone, simplifies the synthesis process of finerenone, reduces half of the yield of finerenone lost during splitting, and thus reduces the production cost of finerenone.

[0005] In order to achieve the above object, a method for preparing finerenone adopted by the present invention comprises the following steps:

[0006]

[0007]

[0008] Step (a) uses the compound of formula 1 and the compound of formula 2 as raw materials to synthesize the compound of formula 3;

[0009] Step (b) reducing the compound of formula 3 under the action of catalysts A and B to obtain a compound of formula 4;

[0010] Step (c) synthesizing a compound of formula 5 by reacting a compound of formula 4 with triethyl orthoformate under acid catalysis;

[0011] Step (d) hydrolyzing the compound of formula 5 with an alkali to synthesize the compound of formula 6;

[0012] Step (e) synthesizing phenarenin of formula 7 from the compound of formula 6 in the presence of hexamethyldisilazane and CDI.

[0013] As an improvement, in the step (a), the compound of formula 1 and the compound of formula 2 are added to sec-butyl alcohol until the compound of formula 2 reacts completely, and then DDQ is added after the temperature is cooled to room temperature to react to obtain the compound of formula 3.

[0014] As an improvement, the molar ratio of the compound of formula 1, the compound of formula 2, sec-butanol and DDQ is (1-1.5):1:(1-1.5):(15-25).

[0015] As an improvement, in the step (b), the compound of formula 3 is added to THF, and then catalysts A and B are added, and the temperature is raised to reflux to react to obtain the compound of formula 4. Wherein, catalyst A is (11BR)-2,6-di-9-anthryl-4-hydroxy-dinaphtho[2,1-D:1',2'-F][1,3,2]dioxyphosphoric acid-4-oxide, CAS: 361342-51-0; B is dihydropyridine, full name: 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester.

[0016] As an improvement, in the step (b), the molar ratio of the compound of formula 3, catalyst A and catalyst B is 1:(0.05-0.15):(1.5-2.5).

[0017] As an improvement, in the step (c), the compound of formula 4, triethyl orthoformate and sulfuric acid are added to DMF, and under the protection of inert gas, the temperature is raised to 100-110° C., stirred for reaction for 2-4 hours, and then cooled to 20-30° C. to obtain the compound of formula 5.

[0018] As an improvement, in step (c), the molar ratio of the compound of formula 4, triethyl orthoformate and sulfuric acid is 1:(4-6):(0.2-0.5).

[0019] As an improvement, in the step (d), after dissolving the compound of formula 5, sodium hydroxide solution is added dropwise, the mixture is stirred while being kept warm, toluene and anhydrous sodium acetate are added, and the pH is adjusted to 6-7 to obtain the compound of formula 6.

[0020] As an improvement, in the step (d), the amount of toluene used is 2-3 times the mass of the compound of formula 5, and the amount of anhydrous sodium acetate used is 20-30% of the mass of the compound of formula 5.

[0021] As an improvement, in the step (e), after dissolving the compound of formula 6, N,N'-carbonyldiimidazole is added, stirred, and hexamethyldisilazane is added to react to obtain finerenone.

[0022] As an improvement, in the step (e), the molar ratio of the compound of formula 6, CDI and hexamethyldisilazane is 1:(1-2):(4-6).

[0023] Compared with the prior art, the method for preparing finerenone of the present invention performs chirality inversion starting from the intermediate, and then obtains the intermediate of the desired chirality, and then synthesizes finerenone from the intermediate. The present invention uses a catalyst for splitting, and does not lose half of the chiral isomers. The catalyst can convert all the raw materials into the desired chiral configuration. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 is the NMR spectrum of the compound of formula 3 in Example 1;

[0025] Figure 2 is the NMR spectrum of the compound of formula 4 in Example 2;

[0026] Figure 3 is the NMR spectrum of the compound of formula 5 in Example 3;

[0027] Figure 4 is the NMR spectrum of the compound of formula 6 in Example 4;

[0028] Figure 5 This is the NMR spectrum of phenerenone in Example 5. DETAILED DESCRIPTION

[0029] The following embodiments are further descriptions of the content of the present invention as an explanation of the technical content of the present invention, but the essential content of the present invention is not limited to the following embodiments. Ordinary technicians in this field can and should know that any simple changes or replacements based on the essential spirit of the present invention should fall within the scope of protection required by the present invention.

[0030] Example 1

[0031]

[0032] Synthetic formula 3 compound:

[0033] At room temperature, 100.00 g of the compound of formula 1 (2-cyanoethyl 2-(4-cyano-2-methoxybenzylidene)-3-oxobutyrate) and 336.41 g of the compound of formula 2 (4-amino-5-methyl-2-hydroxypyridine) were added to 2000 ml of sec-butanol, mechanically stirred, heated to 100 ° C and refluxed, stirred for 16 hours, and the reaction of the compound of formula 2 was detected to be complete. After cooling to room temperature, 182.92 g of DDQ (2,3-dichloro-5,6-dicyanobenzoquinone) was added and stirred at room temperature for 1 hour; the reaction solution was stirred and filtered, and the filter cake was rinsed with 150 mL of sec-butanol, and the filter cake was dried to obtain 310.00 g of the compound of formula 3, with a detection purity of 98% and a yield of 95.1%.

[0034] like Figure 1As shown, the compound of formula 3, H-NMR (400 MHz, DMSO-d6): 11.40 (d, J = 5.6 Hz, 1H), 7.44 (d, J = 1.2 Hz, 1H), 7.39 (dd, J = 8.0, 1.2 Hz, 1H), 7.34 (d, J = 5.2 Hz, 1H), 4.13-4.10 (m, 1H), 4.06-4.02 (m, 1H), 3.68 (s, 3H), 2.72-2.69 (m, 1H), 2.64 (s, 3H), 2.63-2.60 (m, 1H), 2.26 (s, 3H).

[0035] Example 2

[0036]

[0037]

[0038] Synthetic formula 4 compound:

[0039] At room temperature, 310.00 g of the compound of formula 3 was added to 8000 ml of THF, mechanically stirred, 51.98 g of catalyst A and 375.66 g of B were added, the temperature was raised to 100°C and refluxed, and the reaction was stirred for 16 hours. It was detected that the compound of formula 3 was completely reacted. After cooling to room temperature, it was concentrated and dried under reduced pressure, and then 10 times ethanol was added to heat and dissolve, and then cooled and recrystallized; suction filtration, the filter cake was rinsed with 1000 ml of ethanol, and the filter cake was dried to obtain 300.00 g of the compound of formula 4, with a detection purity of 97.0% and a yield of 96.2%.

[0040] like Figure 2 As shown, the compound of formula 4, H-NMR (400 MHz, DMSO-d6): 10.76 (s, 1H), 8.17 (s, 1H), 7.32-7.30 (m, 2H), 7.23 (dd, J = 8.0, 1.6 Hz, 1H), 6.95 (s, 1H), 5.20 (s, 1H), 4.12-4.10 (m, 1H), 4.06-4.02 (m, 1H), 3.74 (s, 3H), 2.82-2.78 (m, 2H), 2.35 (s, 3H), 2.03 (s, 3H).

[0041] Example 3

[0042]

[0043] Compound of Synthetic Formula 5:

[0044] At room temperature, 300.00 g of compound 4, 329.80 g of triethyl orthoformate and 21.83 g of sulfuric acid were added to 1800 ml of DMF, mechanically stirred and protected by argon (nitrogen) gas. The reaction solution was heated to 105°C and stirred for 3 h. The temperature was lowered to 25°C, 5700 mL of water was added dropwise to crystallize. After the addition was completed, the mixture was stirred at 5°C for another 1 h, filtered, and the filter cake was washed with 1200 mL of water and dried at 60°C to obtain 289.6 g of compound 5 with a purity of 98.3% and a yield of 90.2%.

[0045] like Figure 3 As shown, the compound of formula 5, H-NMR (400MHz.DMSO-d6): 8.39 (s, 1H), 7.60 (s, 1H), 7.33-7.30 (m, 2H), 7.25 (ddJ=6.4, 1.2Hz, 1H), 5.37 (s, 1H), 4.09-4.04 (m, 4H, 3.78 (s, 3H), 2.81-2.73 (m, 2H), 2.42 (s, 3H), 2.16 (s, 3H), 1.11 (t, J=6.8Hz, 3H).

[0046] Example 4

[0047]

[0048] Synthetic formula 6 compound:

[0049] At room temperature, 280.00 g of compound 5, 1680 mL of tetrahydrofuran and 840 mL of purified water were added to a 5 L four-necked reaction bottle and mechanically stirred at 3 ° C. Sodium hydroxide solution (2 mol of sodium hydroxide was prepared as an aqueous solution) was added dropwise. After the addition was completed, the mixture was kept at 3 ° C and stirred. After stirring for 1 h, the reaction solution was stirred, 560 g of toluene and 70 g of anhydrous sodium acetate were added. After sufficient stirring, the organic layer was separated, the aqueous layer was collected, and the pH was adjusted to 6.5 with dilute hydrochloric acid. After the adjustment was completed, a solid was precipitated, the temperature was raised to 25 ° C, stirred for 1 h, and filtered. After the filter cake was washed with 1000 mL of water, the filter cake was dried at 60 ° C in vacuum to obtain 243.7 g of compound 6 with a purity of 96.9% and a yield of 99.2%.

[0050] like Figure 4 As shown, the compound of formula 6, H-NMR (400MHz.DMSO-d6): 11.15 (δ, 1H), 8.14 (s, 1H), 7.57 (s, 1H), 7.31 (s, 1H), 7.26 (s, 1H), 5.33 (s, 1H), 4.10-3.99 (m, 2H), 3.73 (s, 3H), 2.37 (s, 3H), 2.14 (s, 3H), 1.11 (t, J = 6.8 Hz, 3H).

[0051] Example 5

[0052]

[0053] Synthetic formula 7-phenaretin:

[0054] At room temperature, 235.00 g of the compound of formula 6 and 1175 mL of tetrahydrofuran were added to a 5L four-necked reaction bottle and mechanically stirred. 140.60 g of N, N'-carbonyldiimidazole was added in batches, paying attention to gas release. After the addition was completed, the mixture was stirred at room temperature for 1 hour, and 299.88 g of hexamethyldisilazane was added. After the addition was completed, nitrogen protection was applied, the temperature was raised to reflux, and the reaction was stirred for 15 hours. The reaction was stopped, the reaction solution was stirred and cooled to below 20°C, 120 mL of water was added dropwise, crystallized, refluxed for another 1 hour, cooled, stirred at 3°C ​​for 1 hour, filtered, and the filter cake was washed with 2350 mL of water. The filter cake was dried at 60°C in vacuum to obtain 201.4 g of phenerenone with a purity of 99.74% and a yield of 85.9%.

[0055] like Figure 5 As shown, the compound of formula 7, phenelenone, H-NMR (400 MHz.DMSO-d6): 7.68 (s, 1H), 7.55 (s, 1H), 7.37 (d, J = 1.2 Hz, 1H), 7.28 (dd, J = 7.6, 1.2 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 6.75-6.69 (m, 2H), 5.38 (s, 1H), 4.04-3.98 (m, 2H), 3.82 (s, 3H), 2.19 (s, 3H), 2.12 (s, 3H), 1.11 (t, J = 7.2 Hz, 3H).

[0056] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing finerenone, characterized in that: The following steps are involved: Step (a) uses the compound of formula 1 and the compound of formula 2 as raw materials to synthesize the compound of formula 3; Step (b) reducing the compound of formula 3 under the action of catalysts A and B to obtain a compound of formula 4; Step (c) synthesizing a compound of formula 5 by reacting a compound of formula 4 with triethyl orthoformate under acid catalysis; Step (d) hydrolyzing the compound of formula 5 with an alkali to synthesize the compound of formula 6; Step (e) synthesizing phenarenin of formula 7 from the compound of formula 6 in the presence of hexamethyldisilazane and CDI.

2. The method for preparing finerenone according to claim 1, characterized in that: In the step (a), the compound of formula 1 and the compound of formula 2 are added to sec-butyl alcohol until the compound of formula 2 reacts completely, and then DDQ is added after the temperature is lowered to room temperature to react to obtain the compound of formula 3.

3. The method for preparing finerenone according to claim 2, characterized in that: The molar ratio of the compound of formula 1, the compound of formula 2, sec-butyl alcohol and DDQ is (1-1.5):1:(1-1.5):(15-25).

4. The method for preparing finerenone according to claim 1, characterized in that: In the step (b), the compound of formula 3 is added to THF, and then catalysts A and B are added, and the temperature is raised to reflux to react to obtain the compound of formula 4.

5. The method for preparing finerenone according to claim 4, characterized in that: In the step (b), the molar ratio of the compound of formula 3, catalyst A and catalyst B is 1: (0.05-0.15): (1.5-2.5).

6. The method for preparing finerenone according to claim 1, characterized in that: In the step (c), the compound of formula 4, triethyl orthoformate and sulfuric acid are added to DMF, and the temperature is raised to 100-110° C. under the protection of inert gas, stirred for reaction for 2-4 hours, and then cooled to 20-30° C. to obtain the compound of formula 5.

7. The method for preparing finerenone according to claim 6, characterized in that: In the step (c), the molar ratio of the compound of formula 4, triethyl orthoformate and sulfuric acid is 1:(4-6):(0.2-0.5).

8. The method for preparing finerenone according to claim 1, characterized in that: In the step (d), after dissolving the compound of formula 5, sodium hydroxide solution is added dropwise, the mixture is stirred while being kept warm, toluene and anhydrous sodium acetate are added, and the pH is adjusted to 6-7 to obtain the compound of formula 6.

9. The method for preparing finerenone according to claim 8, characterized in that: In the step (d), the amount of toluene used is 2-3 times the mass of the compound of formula 5, and the amount of anhydrous sodium acetate used is 20-30% of the mass of the compound of formula 5.

10. The method for preparing finerenone according to claim 1, characterized in that: In the step (e), after dissolving the compound of formula 6, N,N'-carbonyldiimidazole is added, stirred, and hexamethyldisilazane is added to react to obtain finerenone.

11. The method for preparing finerenone according to claim 10, characterized in that: In the step (e), the molar ratio of the compound of formula 6, CDI and hexamethyldisilazane is 1:(1-2):(4-6).

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