A method of preparing finerenone
By simplifying the synthesis process of fenelinone, starting from the intermediate through chiral reversal and using a specific catalyst for resolution, the problems of complexity and yield loss in the synthesis of fenelinone in the prior art are solved, thereby achieving the effect of reducing production costs and increasing yield.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- ZHONGSHAN BAISHENG BIOTECHNOLOGY CO LTD
- Filing Date
- 2024-12-18
- Publication Date
- 2026-07-31
AI Technical Summary
Existing methods for preparing fenelone involve complex synthesis processes, resulting in a loss of half the yield during fenelone resolution and increased production costs.
A simplified synthetic process is employed, starting with chiral inversion from an intermediate and resolving it using a specific catalyst to avoid loss of chiral isomers. The specific steps include reacting compound 1 with compound 2 to generate compound 3, then reducing it with catalysts A and B to generate compound 4, followed by acid catalysis to generate compound 5, alkaline hydrolysis to generate compound 6, and finally reacting it with CDI and hexamethyldisilazane to generate phenelzine.
It reduces the loss of fenelone during the resolution process, lowers production costs, and increases yield and purity.
Smart Images
Figure CN119684289B_ABST
Abstract
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 (BAY 94-8862) is a nonsteroidal selective mineralocorticoid receptor antagonist that has been shown in preclinical studies to block the harmful effects of excessive mineralocorticoid receptor activation. In diabetic patients, excessive mineralocorticoid receptor activation is thought to contribute to the progression of chronic kidney disease and cardiovascular damage, which may be driven by metabolic, hemodynamic, or inflammatory and fibrotic factors.
[0003] Existing methods for preparing fenelinone involve complex synthesis processes and significant yield losses during resolution, resulting in high production costs. Summary of the Invention
[0004] To address the problems existing in the prior art, the present invention provides a method for preparing fenelone, which simplifies the synthesis process of fenelone, reduces the yield lost during the resolution of fenelone by half, and thus reduces the production cost of fenelone.
[0005] To achieve the above objectives, the present invention provides a method for preparing fenelazol, comprising the following steps:
[0006] , ;
[0007] ;
[0008] Step (a) uses compounds of formula 1 and formula 2 as raw materials to synthesize compound 3;
[0009] Step (b) involves reducing compound 3 under the action of catalysts A and B to obtain compound 4;
[0010] Step (c) involves synthesizing compound 5 from compound 4 and triethyl orthoformate under acid catalysis;
[0011] Step (d) involves synthesizing compound 6 by alkaline hydrolysis of compound 5;
[0012] Step (e) involves synthesizing fenelone of formula 7 from compound 6 under the action of hexamethyldisilazane and CDI.
[0013] As an improvement, in step (a), the compound of formula 1 and the compound of formula 2 are added to sec-butanol until the compound of formula 2 reacts completely, and then DDQ is added after cooling to room temperature 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 step (b), the compound of formula 3 is added to THF, followed by catalysts A and B, and the mixture is heated to reflux to react and obtain the compound of formula 4. 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.
[0016] As an improvement, in step (b), the molar ratio of compound of formula 3, catalyst A, and B is 1:(0.05-0.15):(1.5-2.5).
[0017] As an improvement, in step (c), the compound of formula 4, triethyl orthoformate, and sulfuric acid are added to DMF, and the mixture is heated to 100-110°C under inert gas protection. o C, stir the reaction for 2-4 hours, then cool to 20-30℃ to obtain compound of formula 5.
[0018] As an improvement, in step (c), the molar ratio of compound of formula 4, triethyl orthoformate, and sulfuric acid is 1:(4-6):(0.2-0.5).
[0019] As an improvement, in step (d), after dissolving the compound of formula 5, sodium hydroxide solution is added dropwise, the mixture is kept warm and stirred, 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 step (d), the amount of toluene is 2-3 times the mass of the compound of formula 5, and the amount of anhydrous sodium acetate is 20-30% of the mass of the compound of formula 5.
[0021] As an improvement, in step (e), after dissolving the compound of formula 6, N,N'-carbonyldiimidazole is added, the mixture is stirred, and hexamethyldisilazane is added to react and give phenelzine.
[0022] As an improvement, in step (e), the molar ratio of compound of formula 6, CDI, and hexamethyldisilazane is 1:(1-2):(4-6).
[0023] Compared with the prior art, the method for preparing fenelone of the present invention involves chiral inversion starting from the intermediate to obtain the intermediate with the desired chirality, and then synthesizing fenelone from the intermediate. The present invention uses catalyst separation to avoid losing half of the chiral isomers. The catalyst can convert all the raw materials into the desired chiral configuration. Attached Figure Description
[0024] Figure 1 The NMR spectrum of compound of formula 3 in Example 1;
[0025] Figure 2 The NMR spectrum of compound of formula 4 in Example 2;
[0026] Figure 3 The NMR spectrum of compound 5 in Example 3;
[0027] Figure 4 The NMR spectrum of compound of formula 6 in Example 4;
[0028] Figure 5 The NMR spectrum of fenelone in Example 5 is shown. Detailed Implementation
[0029] 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.
[0030] Example 1
[0031] ;
[0032] Synthetic compound 3:
[0033] At room temperature, 336.41 g of compound 1 (2-cyanoethyl 2-(4-cyano-2-methoxybenzyl)-3-oxobutyrate) and 100.00 g of compound 2 (4-amino-5-methyl-2-hydroxypyridine) were added to 2000 mL of sec-butanol. The mixture was mechanically stirred, heated to 100 °C and refluxed. After stirring for 16 h, the reaction of compound 2 was confirmed to be complete. After cooling to room temperature, 182.92 g of DDQ (2,3-dichloro-5,6-dicyano-p-benzoquinone) was added, and the mixture was stirred at room temperature for 1 h. The reaction solution was stirred, filtered, and the filter cake was washed with 150 mL of sec-butanol and dried to obtain 310.00 g of compound 3. The purity was 98% and the yield was 95.1%.
[0034] like Figure 1As shown, the compound of formula 3, H-NMR (400MHz, DMSO-d6): 11.40 (d, J=5.6Hz, 1H), 7.44 (d, J=1.2Hz, 1H), 7.39 (dd, J=8.0, 1.2Hz, 1H), 7.34 (d, J=5.2Hz, 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] Compound of formula 4:
[0039] At room temperature, 310.00 g of compound 3 was added to 8000 ml of THF, mechanically stirred, and then 51.98 g of catalyst A and 375.66 g of catalyst B were added. The temperature was then increased by 100°C. o After refluxing at C and stirring for 16 hours, the reaction of compound 3 was confirmed to be complete. After cooling to room temperature, the mixture was concentrated and dried under reduced pressure. Then, 10 times the amount of ethanol was added and heated to dissolve the compound. After cooling, the mixture was recrystallized. The mixture was filtered, and the filter cake was washed with 1000 ml of ethanol. The filter cake was then dried to obtain 300.00 g of compound 4. The purity was 97.0% and the yield was 96.2%.
[0040] like Figure 2 As shown, the compound of formula 4, H-NMR (400MHz, DMSO-d6): 10.76(s, 1H), 8.17(s, 1H), 7.32-7.30(m, 2H), 7.23(dd, J=8.0, 1.6Hz, 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 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. The mixture was mechanically stirred under argon (nitrogen) protection, and the reaction solution was heated to 105 °C. o C, stir the reaction for 3 hours, cool to 25°C, add 5700 mL of water dropwise, crystallization occurs, after the addition is complete, 5 o Stir for another 1 hour, filter, wash the filter cake with 1200 mL of water, and then blow air at 60°C. o After drying at C, 289.6 g of compound 5 with a purity of 98.3% and a yield of 90.2% were obtained.
[0045] like Figure 3 As shown, compound 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 compound 6:
[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 flask and mechanically stirred. o C. Add sodium hydroxide solution (2 mol sodium hydroxide solution prepared as an aqueous solution). After the addition is complete, keep warm for 3 minutes. o Stirring at C for 1 hour, then maintaining stirring, add 560g toluene and 70g anhydrous sodium acetate. After thorough stirring, separate the organic layer and collect the aqueous layer. Adjust the pH to 6.5 with dilute hydrochloric acid. Once adjusted, a solid precipitates and the solution is heated to 25°C. o C. Stir for 1 hour, filter, wash the filter cake with 1000 mL of water, and then vacuum-filter the filter cake at 60°C. o 243.7 g of compound of formula 6 was obtained by drying at C, with a purity of 96.9% and a yield of 99.2%.
[0050] like Figure 4 As shown, compound 6, ¹H-NMR (400MHz, DMSO-d6): 11.15 (δ, 1H), 8.14 (s, 1H).
[0051] 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=6.8Hz,3H).
[0052] Example 5
[0053] ;
[0054] Synthetic formula 7 fenelazone:
[0055] At room temperature, 235.00 g of compound 6 and 1175 mL of tetrahydrofuran were added to a 5 L four-necked reaction flask and mechanically stirred. 140.60 g of N,N'-carbonyldiimidazole was added in portions, taking care to release gas. After the addition was complete, the mixture was stirred at room temperature for 1 h, then 299.88 g of hexamethyldisilazane was added. After the addition was complete, the mixture was placed under nitrogen protection, heated to reflux, and stirred for 15 h. The reaction was then stopped, and the reaction solution was stirred and cooled to 20 °C. o Below 3°C, add 120 mL of water dropwise to induce crystallization, then reflux for 1 hour, cool, and repeat. o Stir for 1 hour, filter, wash the filter cake with 2350 mL of water, and then vacuum the filter cake at 60°C. o 201.4 g of fenelone was obtained by drying at C, with a purity of 99.74% and a yield of 85.9%.
[0056] like Figure 5 As shown, compound phenelzine (Formula 7) has the following ¹H NMR spectra (400 MHz, DMSO-d⁶): 7.68 (s, 1H), 7.55.
[0057] (s,1H),7.37(d,J=1.2Hz,1H),7.28(dd,J=7.6,1.2Hz,1H),7.14(d,J=7.6Hz,1H),6.75-6.69(m,2 H),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=7.2Hz,3H).
[0058] 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 method for preparing phenelzine, characterized in that, Includes the following steps: ， ； ； Step (a) uses compounds of formula 1 and formula 2 as raw materials to synthesize compound 3; Step (b) involves reducing compound 3 under the action of catalysts A and B to obtain compound 4; Step (c) involves synthesizing compound 5 from compound 4 and triethyl orthoformate under acid catalysis; Step (d) involves synthesizing compound 6 by alkaline hydrolysis of compound 5; Step (e) involves synthesizing phenelzine (formula 7) from compound 6 under the action of hexamethyldisilazane and CDI. In step (a), compound 1 and compound 2 are added to sec-butanol until compound 2 reacts completely. After cooling to room temperature, DDQ is added to react and compound 3 is obtained. The molar ratio of compound 1, compound 2, sec-butanol, and DDQ is (1-1.5):1:(1-1.5):(15-25). Step (b) specifically includes: at room temperature, 310.00g of compound 3 is added to 8000ml of THF, mechanically stirred, and 51.98g of catalyst A and 375.66g of catalyst B are added. The CAS number of catalyst A is 361342-51-0. The temperature is increased by 100°C. o After refluxing at C and stirring for 16 hours, the reaction of compound 3 was confirmed to be complete. The mixture was then cooled to room temperature, concentrated under reduced pressure, and dried. Ten times the volume of ethanol was added, and the mixture was heated to dissolve the compound. After cooling and recrystallization, the mixture was filtered, washed with 1000 ml of ethanol, and dried to obtain 300.00 g of compound 4. The purity was 97.0%, and the yield was 96.2%. In step (e), after dissolving the compound of formula 6, N,N'-carbonyldiimidazole CDI is added, stirred, and hexamethyldisilazane is added to react and phenelzine is obtained. In step (e), the molar ratio of compound of formula 6, CDI and hexamethyldisilazane is 1:(1-2):(4-6).
2. The method for preparing phenelzine according to claim 1, characterized in that, In step (c), the compound of formula 4, triethyl orthoformate, and sulfuric acid are added to DMF, and the mixture is heated to 100-110°C under inert gas protection. o C, stir the reaction for 2-4 hours, cool to 20-30℃, and the reaction yields compound 5.
3. The method for preparing phenelzine according to claim 2, characterized in that, In step (c), the molar ratio of compound of formula 4, triethyl orthoformate, and sulfuric acid is 1:(4-6):(0.2-0.5).
4. The method for preparing phenelzine according to claim 1, characterized in that, In step (d), after dissolving the compound of formula 5, sodium hydroxide solution is added dropwise, the mixture is kept warm and stirred, toluene and anhydrous sodium acetate are added, and the pH is adjusted to 6-7 to obtain the compound of formula 6.
5. The method for preparing phenelzine according to claim 4, characterized in that, In step (d), the amount of toluene used is 2-3 times the mass of compound 5, and the amount of anhydrous sodium acetate used is 20-30% of the mass of compound 5.