Preparation method of fenerenone

Abstract

The preparation method comprises the following steps: dissolving a compound in a formula 1 and a compound in a formula 2 in a solvent, adding piperidine and acetic acid, and carrying out carbon-carbon coupling to synthesize a compound in a formula 3; dissolving the compound in the formula 3 and the compound in the formula 4 in a solvent, and performing ring closing to synthesize a compound in a formula 5; dissolving the compound as shown in the formula 5 into a solvent, adding triethyl orthoformate, and performing alkylation reaction under the catalysis of acid to synthesize a compound as shown in a formula 6; dissolving the compound of formula 6 in a solvent, adding DDQ, and synthesizing a compound of formula 7; dissolving the compound as shown in the formula 7 in a solvent, and performing NaOH hydrolysis to synthesize a compound as shown in a formula 8; dissolving the compound as shown in the formula 8 into a solvent, and carrying out ammonification reaction under the action of CDI and hexamethyldisilazane to synthesize a compound as shown in a formula 9; and dissolving the compound shown in the formula 9 into a solvent, and carrying out reductive resolution under the action of catalysts A and B to synthesize the fenerenone shown in the formula 10. The preparation method of the fenerenone has the advantages of high chiral selectivity, no need of chromatographic column separation, high yield, low cost and the like.

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 is a nonsteroidal selective mineralocorticoid receptor antagonist. In diabetic patients, overactivation of mineralocorticoid receptors is believed to lead to the progression of chronic kidney disease and cardiovascular damage. Preclinical studies have shown that finerenone can block the harmful effects caused by overactivation of mineralocorticoid receptors.

[0003] The prior art has described the process for synthesizing finerenone:

[0004] Patent CN107849043A finerenone synthesis route is as follows:

[0005]

[0006] In this route, the second step reaction, high temperature ring closure of isobutyl alcohol, requires high temperature and high pressure to react, and industrial production has a high risk factor. The final step of separation uses a chiral preparative column, which has a high industrial cost.

[0007] Patent CN106795155A finerenone synthesis route is as follows:

[0008]

[0009] Although this route is improved and does not require high-pressure reaction, which reduces the risk of industrial production, the chiral separation still uses a chiral preparative column, which is difficult to produce on a large scale, and half of the separation is lost, the yield is relatively low, and the cost is relatively high. Summary of the invention

[0010] In view of the problems existing in the above-mentioned prior art, the present invention provides a method for preparing finerenone, which improves the yield and reduces the cost.

[0011] In order to achieve the above object, a method for preparing finerenone adopted by the present invention comprises the following steps:

[0012]

[0013]

[0014] Step (a) dissolving the compound of formula 1 and the compound of formula 2 in a solvent, adding piperidine and acetic acid, and performing carbon-carbon coupling to synthesize the compound of formula 3;

[0015] Step (b) dissolving the compound of formula 3 and the compound of formula 4 in a solvent, and performing ring closing to synthesize the compound of formula 5;

[0016] Step (c) dissolving the compound of formula 5 in a solvent, adding triethyl orthoformate, and carrying out an alkylation reaction under acid catalysis to synthesize the compound of formula 6;

[0017] Step (d) dissolving the compound of formula 6 in a solvent, adding DDQ to synthesize the compound of formula 7;

[0018] Step (e) dissolving the compound of formula 7 in a solvent and hydrolyzing it with NaOH to synthesize the compound of formula 8;

[0019] Step (f) dissolving the compound of formula 8 in a solvent, and subjecting it to an amination reaction under the action of CDI and hexamethyldisilazane to synthesize the compound of formula 9;

[0020] Step (g) dissolving the compound of formula 9 in a solvent, and asymmetric reducing the compound in the presence of catalysts A and B to synthesize phenarenin of formula 10; wherein catalyst A is (11BR)-2,6-di-9-anthracenyl-4-hydroxy-dinaphtho[2,1-D:1',2'-F][1,3,2]dioxyphosphoric acid-4-oxide, CAS: 361342-51-0; and B is dihydropyridine, full name: 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester.

[0021] Preferably, in step (a), the molar ratio of the compound of formula 1, the compound of formula 2, piperidine and acetic acid is 1:(1-1.5):(0.05-0.2):(0.05-0.2).

[0022] Preferably, in step (a), DCM is used as the solvent; and / or the reaction temperature is 45-50° C.; and / or the reaction is carried out under reflux stirring.

[0023] Preferably, in the step (b), the molar ratio of the compound of formula 3 to the compound of formula 4 is 1:(1-1.5).

[0024] Preferably, in the step (b), sec-butyl alcohol is used as the solvent; and / or the reaction temperature is 95-100° C.; and / or the reaction is carried out under reflux and stirring.

[0025] Preferably, in step (c), sulfuric acid is used as a catalyst, and the molar ratio of the compound of formula 5, triethyl orthoformate, and sulfuric acid is 1:(2-5):(0.2-0.5).

[0026] Preferably, in step (c), DMF is used as solvent; and / or the reaction temperature is 100-110° C.; and / or the reaction is carried out under nitrogen protection.

[0027] Preferably, in the step (d), the molar ratio of the compound of formula 6 to DDQ is 1:(1-1.5); and / or, DCM is used as the solvent; and / or, the reaction is stirred at room temperature.

[0028] Preferably, in the step (e), the molar ratio of the compound of formula 7 to NaOH is 1:(1-3); and / or THF is used as the solvent.

[0029] Preferably, in step (f), the molar ratio of the compound of formula 8, CDI and hexamethyldisilazane is 1:(1-1.5):(2-5); and / or THF is used as the solvent; and / or the reaction temperature is 70-80°C; and the reaction is refluxed and stirred.

[0030] Preferably, in step (g), the molar ratio of the compound of formula 9 to catalysts A and B is 1:(0.05-0.2):(1-1.5); and / or THF is used as solvent; and / or the reaction temperature is 70-80°C; and / or the reaction is refluxed and stirred.

[0031] Compared with the prior art, the preparation method of finerenone of the present invention does not require high-pressure reaction, adopts asymmetric reduction, avoids chiral preparation column separation, has high utilization rate and high yield, saves some operating procedures, and greatly reduces production costs. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 The compound of formula 3 synthesized in Example 1 1 H-NMR;

[0033] Figure 2 The compound of formula 5 synthesized in Example 2 1 H-NMR;

[0034] Figure 3 The compound of formula 6 synthesized in Example 3 1 H-NMR;

[0035] Figure 4 The compound of formula 8 synthesized in Example 5 1 H-NMR;

[0036] Figure 5 The compound of formula 9 synthesized in Example 6 1 H-NMR;

[0037] Figure 6 The finerenone of formula 10 synthesized in Example 7 1 H-NMR. DETAILED DESCRIPTION

[0038] 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.

[0039] Example 1

[0040]

[0041] Synthetic formula 3 compound:

[0042] At room temperature, 1000.00g of the compound of formula 1 (4-cyano-2-methoxybenzaldehyde), 792.58g of the compound of formula 2 (methyl acetoacetate), 52.84g of piperidine and 37.26g of acetic acid were added to 10L of DCM, mechanically stirred, heated to 48°C, refluxed and stirred to react, and the reaction of the compound of formula 1 was detected to be complete. After cooling to room temperature, 5L of water was added and stirring was maintained. The mixture was allowed to stand for stratification, and the organic layer was collected and concentrated to dryness at 60°C under reduced pressure to obtain 1517.32g of the compound of formula 3 with a detection purity of 98.2% and a yield of 94.3%. 1 H-NMR (400MHz, DMSO-d6): 7.82 (s, 1H), 7.62 (d, J = 1.2 Hz, 1H), 7.48 (dd, J = 1.2 Hz, 1H), 7.41 (d, J = 8 Hz, 1H), 3.91 (s, 3H), 3.69 (s, 3H), 2.43 (s, 3H).

[0043] Example 2

[0044]

[0045] Compound of Synthetic Formula 5:

[0046] At room temperature, 1517.30g of compound 3 and 799.17g of compound 4 (4-amino-5-methyl-2-hydroxypyridine) were added to 15L of sec-butanol, and the mixture was stirred mechanically. The temperature was raised to 95°C and refluxed with stirring for reaction. The reaction of compound 3 was detected to be complete. After cooling to room temperature, the mixture was filtered with suction, and the filter cake was rinsed with 3L of sec-butanol and then collected. The collected filter cake was dried at 70°C by blowing to obtain 2003.37g of compound 5 with a detection purity of 97.8% and a yield of 93.7%.

[0047] 1H-NMR (400MHz, DMSO-d6): 10.74 (s, 1H), 8.08 (s, 1H), 7.32 (d, J = 1.2Hz, 1H), 7.25 (dd, J = 1.2Hz, 1.6Hz, 1 H), 7.18(d,J=7.6Hz,1H), 6.95(s,1H), 5.24(s,1H), 3.75(s,3H), 3.50(s,3H), 2.30(s,3H), 2.03(s,3H).

[0048] Example 3

[0049]

[0050] Synthetic formula 6 compound:

[0051] At room temperature, 2003.30g of compound 5, 2437.58g of triethyl orthoformate and 161.32g of sulfuric acid were added to 12LDMF, mechanically stirred and protected with nitrogen. The temperature was raised to 105°C and stirred for reaction. The reaction of compound 5 was detected to be complete. After cooling to room temperature, 38L of water was added dropwise for crystallization. After the addition was completed, the filter cake was washed with 12L of water and collected. The collected filter cake was dried at 70°C with air blowing to obtain 1980.22g of compound 6 with a detection purity of 97.2% and a yield of 91.8%. 1 H-NMR (400MHz, DMSO-d6): 8.26 (s, 1H), 7.59 (s, 1H), 7.32 (s, 1H), 7.26 (dd, J = 1.2Hz, 0.8Hz, 1H), 7.22 (d, J = 7.6Hz ,1H), 5.38(s,1H), 4.08-3.98(m,2H), 3.78(s,3H), 3.47(s,3H), 2.38(s,3H), 2.15(s,3H), 1.10(t,J=6.8Hz,3H).

[0052] Example 4

[0053]

[0054] Synthetic formula 7 compound:

[0055] At room temperature, 1980.20 g of the compound of formula 6 and 1371.00 g of DDQ (2,3-dichloro-5,6-dicyanobenzoquinone) were added to 20 L of DCM and mechanically stirred. The reaction of the compound of formula 6 was detected to be complete, filtered, the filtrate was collected, and the solvent was concentrated under reduced pressure. The mixture was slurried with 10 L of methanol and filtered. The filter cake was washed with 1 L of methanol and then collected. The collected filter cake was dried at 70 ° C with air blowing to obtain 1777.02 g of the compound of formula 7 with a detection purity of 96.9% and a yield of 90.2%.

[0056] Example 5

[0057]

[0058] Synthetic formula 8 compound:

[0059] At room temperature, 1777.00g of compound 7, 11L of tetrahydrofuran and 5L of water were mechanically stirred, and NaOH solution (prepared by dissolving 363.18g of NaOH in 5L of water) was added dropwise. After the addition was completed, the mixture was kept warm and stirred. After the reaction of compound 7 was detected to be complete, 5L of toluene and 337.63g of anhydrous sodium acetate were added, stirred, and the mixture was allowed to stand to separate the aqueous layer. The pH of the aqueous layer was adjusted to 6.5 with dilute hydrochloric acid (prepared by adding 360mL of hydrochloric acid to 4L of water). After the adjustment was completed, precipitated, 3642.85g of ammonium chloride and 5L of water were added, and further crystallized. The mixture was filtered with suction, and the filter cake was rinsed with 10L of water and then collected. The collected filter cake was dried at 70°C with air blowing to obtain 1677.35g of compound 8 with a detection purity of 97.0% and a yield of 97.9%.

[0060] 1 H-NMR (400MHz, DMSO-d6): 13.41 (s, 1H), 8.08 (s, 1H), 7.55 (s, 1H), 7.49 (dd, J = 1.2Hz, 1H), 7.26 ( d,J=7.6Hz,1H), 4.08-3.95(m,2H), 3.67(s,3H), 2.71(s,3H), 2.51(s,3H), 0.72(t,J=7.2Hz,3H).

[0061] Example 6

[0062]

[0063] Synthetic formula 9 compound:

[0064] At room temperature, 1677.30 g of compound 8, 792.72 g of CDI (N, N'-carbonyldiimidazole) and 2151.82 g of hexamethyldisilazane were added to 9 L of tetrahydrofuran, mechanically stirred, heated to 75 ° C, stirred for reaction, and the reaction of compound 8 was detected to be complete. The temperature was lowered to below 20 ° C, 850 mL of water was added dropwise, and the reaction was completed. The temperature was stirred at 75 ° C for 1 h, then lowered to 5 ° C, stirred for 1 h, filtered, and the filter cake was rinsed with 20 L of water and collected. The collected filter cake was dried at 70 ° C by blowing to obtain 1447.10 g of compound 9 with a detection purity of 99.74% and a yield of 86.5%.

[0065] 1H-NMR (400MHz, DMSO-d6): 8.04(d,J=1.2Hz,1H), 7.71(brs,1H), 7.51(s,2H), 7.46(dd,J=1.2Hz,1H), 7 .31(d,J=7.6Hz,1H), 4.06-3.92(m,2H), 3.65(s,3H), 2.70(s,3H), 2.50(s,3H), 0.71(t,J=7.2Hz,3H).

[0066] Example 7

[0067]

[0068]

[0069] Phenelide of synthetic formula 10:

[0070] At room temperature, 1447.05 g of the compound of formula 9, 269.38 g of catalyst A, and 952.47 g of compound B were added to 15 L of tetrahydrofuran, mechanically stirred, heated to 75 ° C, stirred for reaction, and the reaction of the compound of formula 9 was detected to be complete. The tetrahydrofuran was evaporated, 30 L of anhydrous ethanol and 80 g of activated carbon were added, stirred for 1 h, and the activated carbon was filtered out. 20 L of ethanol was evaporated from the filtrate, crystallized, filtered, and the filter cake was washed with 2 L of anhydrous ethanol and collected. The collected filter cake was dried at 70 ° C with air blowing to obtain 1223.47 g of phenerenone of formula 10, with a detection purity of 99.86%, ee = 99.9%, and a yield of 84.1%. 1 H-NMR (400MHz, DMSO-d6): 7.69(s,1H), 7.55(s,1H), 7.37(d,J=1.2Hz,1H), 7.28(dd,J=1.2Hz, 1.6Hz,1H), 7.15(d,J=8H z,1H), 6.76-6.68(m,2H), 5.38(s,1H), 4.04-3.98(m,2H), 3.82(s,3H), 2.19(s,3H), 2.12(s,3H), 1.05(t,J=7.2Hz,3H).

[0071] The preparation method of finerenone of the present invention has the advantages of high chiral selectivity, no need for chromatographic column separation, high yield, low cost and the like.

[0072] 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) dissolving the compound of formula 1 and the compound of formula 2 in a solvent, adding piperidine and acetic acid, and performing carbon-carbon coupling to synthesize the compound of formula 3; Step (b) dissolving the compound of formula 3 and the compound of formula 4 in a solvent, and performing ring closing to synthesize the compound of formula 5; Step (c) dissolving the compound of formula 5 in a solvent, adding triethyl orthoformate, and carrying out an alkylation reaction under acid catalysis to synthesize the compound of formula 6; Step (d) dissolving the compound of formula 6 in a solvent, adding DDQ to synthesize the compound of formula 7; Step (e) dissolving the compound of formula 7 in a solvent and hydrolyzing it with NaOH to synthesize the compound of formula 8; Step (f) dissolving the compound of formula 8 in a solvent, and subjecting it to an amination reaction under the action of CDI and hexamethyldisilazane to synthesize the compound of formula 9; Step (g) The compound of formula 9 is dissolved in a solvent, and asymmetric reduction is performed under the action of catalysts A and B to synthesize phenerenone of formula 10.

2. The method for preparing finerenone according to claim 1, characterized in that: In the step (a), the molar ratio of the compound of formula 1, the compound of formula 2, piperidine and acetic acid is 1:(1-1.5):(0.05-0.2):(0.05-0.2).

3. A method for preparing finerenone according to claim 1 or 2, characterized in that: In the step (a), DCM is used as the solvent; and / or the reaction temperature is 45-50° C.; and / or the reaction is refluxed and stirred.

4. The method for preparing finerenone according to claim 1, characterized in that: In the step (b), the molar ratio of the compound of formula 3 to the compound of formula 4 is 1:(1-1.5).

5. The method for preparing finerenone according to claim 1 or 4, characterized in that: In the step (b), sec-butyl alcohol is used as the solvent; and / or the reaction temperature is 95-100° C.; and / or the reaction is carried out under reflux and stirring.

6. The method for preparing finerenone according to claim 1, characterized in that: In the step (c), sulfuric acid is used as a catalyst, and the molar ratio of the compound of formula 5, triethyl orthoformate, and sulfuric acid is 1:(2-5):(0.2-0.5).

7. The method for preparing finerenone according to claim 1 or 6, characterized in that: In the step (c), DMF is used as the solvent; and / or the reaction temperature is 100-110° C.; and / or the reaction is carried out under nitrogen protection.

8. The method for preparing finerenone according to claim 1, characterized in that: In the step (d), the molar ratio of the compound of formula 6 to DDQ is 1:(1-1.5); and / or, DCM is used as the solvent; and / or, the reaction is stirred at room temperature.

9. The method for preparing finerenone according to claim 1, characterized in that: In the step (e), the molar ratio of the compound of formula 7 to NaOH is 1:(1-3); and / or THF is used as the solvent.

10. The method for preparing finerenone according to claim 1, characterized in that: In the step (f), the molar ratio of the compound of formula 8, CDI and hexamethyldisilazane is 1:(1-1.5):(2-5); and / or THF is used as the solvent; and / or the reaction temperature is 70-80° C.; and / or the reaction is refluxed and stirred.

11. The method for preparing finerenone according to claim 1, characterized in that: In the step (g), the molar ratio of the compound of formula 9 to the catalysts A and B is 1:(0.05-0.2):(1-1.5); and / or, THF is used as the solvent; and / or, the reaction temperature is 70-80° C.; and / or, the reaction is refluxed and stirred.

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