Process for the preparation of finerenone

Abstract

This invention discloses a method for preparing phenelzine, comprising the following steps: dissolving compounds of formula 1 and formula 2 in a solvent, adding piperidine and acetic acid, and performing carbon-carbon coupling to synthesize compound 3; dissolving compounds of formula 3 and formula 4 in a solvent, performing cyclization to synthesize compound 5; dissolving compound 5 in a solvent, adding triethyl orthoformate, and performing alkylation under acid catalysis to synthesize compound 6; dissolving compound 6 in a solvent, adding DDQ to synthesize compound 7; dissolving compound 7 in a solvent, and hydrolyzing it with NaOH to synthesize compound 8; dissolving compound 8 in a solvent, and performing amination under the action of CDI and hexamethyldisilazane to synthesize compound 9; dissolving compound 9 in a solvent, and performing reduction resolution under the action of catalysts A and B to synthesize phenelzine of formula 10. The method for preparing phenelzine of this invention has advantages such as high chiral selectivity, no need for column chromatography separation, high yield, and low cost.

Description

Technical Field

[0001] This invention relates to a method for preparing fenelazol, belonging to the field of pharmaceutical preparation technology. Background Technology

[0002] Finerenone is a nonsteroidal selective mineralocorticoid receptor antagonist. In diabetic patients, overactivation of mineralocorticoid receptors is thought 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 synthesis process of fenelone has been described in existing technologies:

[0004] The synthetic route for fenelazol in patent CN107849043A is as follows:

[0005]

[0006] In this route, the second step, the high-temperature ring closure of sec-butanol, requires high temperature and high pressure to react, which poses a high risk for industrial production. The final step, the resolution, uses a chiral preparative column, which increases the cost of industrialization.

[0007] The synthetic route for fenelazol (patent CN106795155A) is as follows:

[0008]

[0009] Although this route has been improved by eliminating the need for high-pressure reactions and reducing the risks of industrial production, chiral separation still uses a chiral preparation column, making it difficult to scale up production. Furthermore, half of the separation is lost, resulting in a relatively low yield and relatively high cost. Summary of the Invention

[0010] To address the problems existing in the prior art, this invention provides a method for preparing fenelone, which improves the yield and reduces the cost.

[0011] To achieve the above objectives, the present invention provides a method for preparing fenelazol, comprising the following steps:

[0012] , ;

[0013] ;

[0014] Step (a) Dissolve the compound of formula 1 and the compound of formula 2 in a solvent, add piperidine and acetic acid, carbon-carbon couple to synthesize the compound of formula 3;

[0015] Step (b) Dissolve compounds of formula 3 and formula 4 in a solvent, close the ring, and synthesize compound 5;

[0016] In step (c), compound 5 is dissolved in a solvent, triethyl orthoformate is added, and alkylation is carried out under acid catalysis to synthesize compound 6.

[0017] Step (d) Dissolve compound 6 in a solvent, add DDQ, and synthesize compound 7;

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

[0019] In step (f), compound 8 is dissolved in a solvent and subjected to an amination reaction in the presence of CDI and hexamethyldisilazane to synthesize compound 9.

[0020] Step (g) The compound of formula 9 is dissolved in a solvent and asymmetrically reduced in the presence of catalysts A and B to synthesize phenelzine of formula 10; wherein, catalyst A is (11BR)-2,6-di-9-anthrayl-4-hydroxy-dinaphthalene[2,1-D:1',2'-F][1,3,2]dioxophosphate-4-oxide, CAS: 361342-51-0; B is dihydropyridine, full name: diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate.

[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. o C; and / or, reflux and stirring reaction.

[0023] Preferably, in 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 step (b), sec-butanol is used as the solvent; and / or, the reaction temperature is 95-100°C. o C; and / or, reflux and stirring reaction.

[0025] Preferably, in step (c), sulfuric acid catalysis is used, 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 the solvent; and / or, the reaction temperature is 100-110 °C. o C; and / or, under nitrogen protection.

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

[0028] Preferably, in 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 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. o C; reflux and stirring reaction.

[0030] Preferably, in step (g), the molar ratio of compound 9 to 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. o C; and / or, reflux and stirring reaction.

[0031] Compared with the prior art, the method for preparing fenelone 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 operation steps, and greatly reduces production costs. Attached Figure Description

[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 fenelone of formula 10 synthesized in Example 7 1 H-NMR. Detailed Implementation

[0038] The following embodiments are further illustrations of the present invention and serve as explanations of the technical content of the present invention. However, the essence of the present invention is not limited to the embodiments described below. Those skilled in the art can and should know that any simple changes or substitutions based on the spirit of the present invention should fall within the protection scope claimed by the present invention.

[0039] Example 1

[0040] ;

[0041] Synthetic compound 3:

[0042] At room temperature, 1000.00 g of compound 1 (4-cyano-2-methoxybenzaldehyde), 792.58 g of compound 2 (methyl acetoacetate), 52.84 g of piperidine, and 37.26 g of acetic acid were added to 10 L of DCM, mechanically stirred, and heated to 48 °C. o C. Reflux and stir the reaction mixture. Detect the complete reaction of compound 1. After cooling to room temperature, add 5 L of water, continue stirring, allow to stand and separate into layers, collect the organic layer, and depressurize to 60 °C. o C was concentrated to dryness to obtain 1517.32 g of compound 3, with a purity of 98.2% and a yield of 94.3%. 1 H-NMR (400MHz, DMSO-d6): 7.82(s,1H), 7.62(d,J=1.2Hz,1H), 7.48(dd,J=1.2Hz,1H), 7.41(d,J=8Hz,1H), 3.91(s,3H), 3.69(s,3H), 2.43(s,3H).

[0043] Example 2

[0044] ;

[0045] Compound of Formula 5:

[0046] At room temperature, 1517.30 g of compound 3 and 799.17 g of compound 4 (4-amino-5-methyl-2-hydroxypyridine) were added to 15 L of sec-butanol, mechanically stirred, and heated to 95 °C. o C. Reflux and stir the reaction mixture until compound 3 is completely reacted. After cooling to room temperature, filter the mixture. Wash the filter cake with 3 L of sec-butanol and collect it. Then, blow the collected filter cake at 70°C. o After drying at C, 2003.37 g of compound 5 was obtained, with a 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,1H), 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 compound 6:

[0051] At room temperature, 2003.30 g of compound 5, 2437.58 g of triethyl orthoformate, and 161.32 g of sulfuric acid were added to 12 LDM, mechanically stirred, and heated to 105 °C under nitrogen protection. o C. Stir the reaction mixture until compound 5 has reacted completely. After cooling to room temperature, add 38 L of water dropwise. Crystallization occurs. After the addition is complete, filter the mixture. Wash the filter cake with 12 L of water and collect it. Then, aerate the collected filter cake at 70°C. o After drying at C, 1980.22 g of compound 6 was obtained, with a 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] Compound of Formula 7:

[0055] At room temperature, 1980.20 g of compound 6 and 1371.00 g of DDQ (2,3-dichloro-5,6-dicyanobenzoquinone) were added to 20 L of DCM. The mixture was mechanically stirred until compound 6 reacted completely. The mixture was filtered, and the filtrate was collected. The solvent was concentrated under reduced pressure, and the mixture was slurried with 10 L of methanol. The mixture was then filtered again, and the filter cake was washed with 1 L of methanol and collected. The collected filter cake was then subjected to a 70°C blower. oAfter drying at C, 1777.02 g of compound 7 was obtained, with a purity of 96.9% and a yield of 90.2%.

[0056] Example 5

[0057] ;

[0058] Synthetic Formula 8 compound:

[0059] At room temperature, 1777.00 g of compound 7, 11 L of tetrahydrofuran, and 5 L of water were mechanically stirred, and NaOH solution (prepared by dissolving 363.18 g of NaOH in 5 L of water) was added dropwise. After the addition was complete, the mixture was kept warm and stirred until the reaction of compound 7 was complete. Then, 5 L of toluene and 337.63 g of anhydrous sodium acetate were added, stirred, and 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 dissolving 360 mL of hydrochloric acid in 4 L of water). After adjustment, precipitate was formed, and 3642.85 g of ammonium chloride and 5 L of water were added for further crystallization. The mixture was filtered, and the filter cake was washed with 10 L of water and collected. The collected filter cake was then subjected to a 70°C blower. o After drying at C, 1677.35 g of compound 8 was obtained, with a 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 =1.2 Hz,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 compound 9:

[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, and heated to 75°C. o C, stirring reaction, detection of compound 8 after complete reaction, temperature reduced to 20. o Below C, add 850mL of water dropwise. After the addition is complete, 75 o Stir at C for 1 hour, then reduce to 5°C. o C. Stir for 1 hour, filter, rinse the filter cake with 20L of water, collect, and then blow air at 70°C. oAfter drying at C, 1447.10 g of compound 9 was obtained, with a purity of 99.74% and a yield of 86.5%.

[0065] 1 H-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] Fennedone, Formula 10:

[0070] At room temperature, 1447.05 g of compound 9, 269.38 g of catalyst A, and 952.47 g of compound B were added to 15 L of tetrahydrofuran, mechanically stirred, and heated to 75 °C. o C. Stir the reaction, detect the complete reaction of compound 9, distill off tetrahydrofuran, add 30L of anhydrous ethanol and 80g of activated carbon, stir for 1h, filter to remove activated carbon, distill off 20L of ethanol from the filtrate, crystallize, filter under vacuum, wash the filter cake with 2L of anhydrous ethanol and collect, the collected filter cake is then blown at 70°C. o After drying at C, 1223.47 g of fenelone of formula 10 was obtained, with a purity of 99.86%, ee=99.9%, and a yield of 84.1%.

[0071] 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=8Hz,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).

[0072] The method for preparing fenelone of the present invention has advantages such as high chiral selectivity, no need for chromatographic column separation, high yield, and low cost.

[0073] 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 or improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A process for the preparation of finerenone, characterized in that, Includes the following steps: ， ； ； Step (a) Dissolve the compound of formula 1 and the compound of formula 2 in the solvent DCM, add piperidine and acetic acid, carbon-carbon coupling to synthesize the compound of formula 3; Step (b) Dissolve compounds of formula 3 and formula 4 in the solvent sec-butanol, cyclize, and synthesize compound 5; In step (c), compound 5 is dissolved in DMF, triethyl orthoformate is added, and alkylation is carried out under sulfuric acid catalysis to synthesize compound 6. Step (d) Dissolve compound 6 in solvent DCM, add DDQ, and synthesize compound 7; Step (e) involves dissolving compound 7 in the solvent THF and hydrolyzing it with NaOH to synthesize compound 8. In step (f), compound 8 is dissolved in solvent THF and subjected to amination reaction in the presence of CDI and hexamethyldisilazane to synthesize compound 9. Step (g) Asymmetric reduction of compound of formula 9 in solvent THF in presence of catalyst A, B to synthesize nonalineketone of formula 10 at temperature 70-80 °C o C; 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). In step (b), the molar ratio of the compound of formula 3 to the compound of formula 4 is 1:(1-1.5). In step (c), sulfuric acid catalysis is used, and the molar ratio of the compound of formula 5, triethyl orthoformate, and sulfuric acid is 1:(2-5):(0.2-0.5). The molar ratio of compound 6 to DDQ is 1:(1-1.5). The molar ratio of compound 7 to NaOH is 1:(1-3); The molar ratio of compound 8, CDI, and hexamethyldisilazane is 1:(1-1.5):(2-5); The molar ratio of compound 9 to catalysts A and B is 1:(0.05-0.2):(1-1.5).

2. A process for the preparation of finerenone according to claim 1, characterized in that, In the step (a), the reaction temperature is 45-50 o C.

3. A process for the preparation of finerenone according to claim 1, characterized in that, In the step (b), the reaction temperature is 95-100 o C.

4. The method for preparing phenelzine according to claim 1, characterized in that, In the step (c), the reaction temperature is 100-110 o C; and / or, under nitrogen protection.

5. The method for preparing phenelzine according to claim 1, characterized in that, In step (d), the reaction is stirred at room temperature.

6. The method for preparing phenelzine according to claim 1, characterized in that, In the step (f), the reaction temperature is 70-80 o C.

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