Method for preparing fenerenone from raceme of fenerenone and refining and crystallizing intermediate

Abstract

The invention discloses a method for preparing fenerenone from a fenerenone raceme and refining and crystallizing an intermediate. Chirally substituted tartaric acid ester is adopted to prepare an intermediate, namely, a non-nepetenone diastereomer salt III, and then the non-nepetenone diastereomer salt III is subjected to alkali dissociation to prepare the non-nepetenone (IIa). According to the invention, by adding a refining and crystallizing method of the intermediate fenerenone diastereomer salt (III), the ee value obtained by the prepared intermediate fenerenone diastereomer salt (III) is higher than 99.5%, and the e.e value in a fenerenone bulk drug further prepared on the basis is basically 100%; a resolving agent tartrate is not detected in the free fenerenone enantiomer, product loss and three-waste generation caused by multiple dissociation are avoided, the production and manufacturing cost is greatly reduced, the product prepared by the method is high in yield and low in three-waste pollution, the preparation process is extremely simple to operate, the reaction condition is mild, the production cost is saved, and the method is suitable for industrial production. The method is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, and specifically relates to a method for preparing phenelzine and purifying and crystallizing intermediates from a racemic phenelzine. Background Technology

[0002] Finerenone, chemical name: (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide, has the following structural formula:

[0003]

[0004] The compound of formula (II) is a racemic mixture of phenelzine:

[0005]

[0006] The term "enantiomers of fenelone" refers to compounds of formulas IIa and IIb, fenelone as a nonsteroidal antagonist of the mineralocorticoid receptor, and can be used as a drug for the prevention and / or treatment of cardiovascular and renal diseases such as heart failure and diabetic nephropathy, wherein only the enantiomer of formula IIa is active.

[0007]

[0008] In the published research-grade synthesis (WO 2008 / 104306 A1), a specially synthesized chiral phase (prepared internally) was used, which contained N-(dicyclopropylmethyl)-N-2-methacryloyl-D-leucamide as a chiral selector.

[0009] It has been found that separation can also be performed on commercially available phases. These are Chiralpak AS-V phases, 20 μm in size, using a 60:40 mixture of methanol and acetonitrile as the eluent. In this case, chromatography can be performed on a conventional column, but techniques known to those skilled in the art, such as SMB, are preferred.

[0010]

[0011] While SMB separation offers relatively good yields and optical purity, the acquisition and operational challenges of such equipment under GMP conditions are significant, resulting in high costs. The chiral phases used are also very expensive and have limited lifespans, requiring frequent replacements in continuous production. This is not optimal for the production process unless a second unit is available to ensure continuous operation, which incurs additional costs. Furthermore, especially with tonne-scale product preparation, solvent recovery is a time-constrained step, requiring the purchase of large falling film evaporators and consuming substantial amounts of energy.

[0012] Patent CN112041318A mentions using D-(+)-dibenzoyl tartaric acid to resolve compound (II) to obtain enantiomers of phenelzine. The method first involves reacting D-(+)-dibenzoyl tartaric acid with the racemic mixture of compound (II) to form diastereomer salts of phenelzine. Then, the pH is adjusted using ethanol / water and sodium phosphate solution, and the mixture is stirred for up to 18 hours to obtain crude phenelzine (IIa). However, the patent also mentions that as the scale is increased, the removal of D-(+)-dibenzoyl tartaric acid from phenelzine (IIa) becomes difficult and requires further processing until it is less than 0.1%.

[0013] Patent CN117986250A mentions using D-(+)-di-o-methylbenzoyl tartaric acid to resolve compound (II) to obtain the diastereomeric salt of phenelzine, and further obtaining crude phenelzine (IIa). The preparation method is similar to that of patent CN112041318A.

[0014] Of the above methods for preparing phenelzine (IIa), the WO2008 / 104306A1 method is limited to the experimental research stage and is difficult to industrialize. Currently, the mainstream methods for preparing phenelzine (IIa) are basically obtained by using chiral substituted diastereotartrate esters to resolve the racemic mixture of phenelzine, as reported in patents CN112041318A and CN117986250A, and then further alkali-free to obtain phenelzine (IIa). However, the existing resolution techniques have the following problems: (1) the purity of the obtained phenelzine diastereotartrate salt ee is not high; (2) the residual impurities of the substituted tartrate esters in the resolving agent fluctuate greatly in multiple batches of phenelzine (IIa), and some have high residual content, requiring further processing.

[0015] As described in the comparative experiment in patent CN117986250A: when D-(+)-dibenzoyl tartaric acid was used to resolve the racemic mixture of phenelzine, the ee value of the diastereomeric salt of phenelzine was 96.7%, and the ee value of the further prepared phenelzine (IIa) was 96.7%, with a residual impurity of 0.50% for the resolving agent D-(+)-di-o-methylbenzoyl tartaric acid; while when D-(+)-di-o-methylbenzoyl tartaric acid was used to resolve the racemic mixture of phenelzine, the ee value of the diastereomeric salt of phenelzine was 97.2%, and the ee value of the further prepared phenelzine (IIa) was 97.0%, with a residual impurity of 0.04% for the resolving agent D-(+)-di-o-methylbenzoyl tartaric acid. Although patent CN117986250A further improved the ee purity of phenelzine diastereomer salt and greatly reduced resolving agent residue, the ee value of phenelzine diastereomer salt still did not reach a good level, and the risk of resolving agent residue still exists. In addition, the resolving agent D-(+)-di-o-methylbenzoyl tartaric acid has not yet achieved large-scale production in the domestic market, and its market price is high.

[0016] To address the problems existing in the prior art, this invention provides a method for preparing feninone from a racemic mixture. The obtained intermediate feninone diastereomeric salt and crude feninone diastereomeric product have an ee value of over 99.5%, and the chiral substituted tartrate ester of the resolving agent is not detected. This greatly reduces the quality risk in the finished product, results in low pollution from production waste, simple post-processing, mild reaction conditions, high product yield and purity, and low cost, making it very suitable for industrial production. Summary of the Invention

[0017] The purpose of this invention is to address the shortcomings of existing technologies by providing a method for preparing phenelzine and its intermediates from a racemic phenelzine mixture, which has mild reaction conditions, simple operation, high product yield and purity, and low production cost, making it very suitable for industrial production.

[0018] One object of the present invention is to provide a method for preparing phenelzine from a racemic mixture of phenelzine, comprising the following steps:

[0019] (1) The racemic phenelzine (II) was reacted with D-(+)-dibenzoyl tartaric acid (IV) in a solvent to prepare the intermediate phenelzine diastereomeric salt (III) wet product, and then purified and crystallized to obtain the refined phenelzine diastereomeric salt (III);

[0020] (2) The intermediate phenelzine diastereomeric salt (III) was prepared into phenelzine (IIa) by alkali release, pH adjustment and post-treatment in a solvent;

[0021] Its synthetic route is as follows:

[0022]

[0023] Preferably, the molar ratio of compound II to compound IV in step (1) is 1:0.5 to 1, more preferably 1:0.5 to 0.65, and the reaction solvent for compound II and compound IV is a mixture of ethanol and water.

[0024] Preferably, the solvent in step (2) is N,N-dimethylformamide, N,N-dimethylacetamide, methanol and water, ethanol and water, or acetonitrile and water, and more preferably a combination of ethanol and water, wherein the volume ratio of ethanol to water is 1:2 to 3:1.

[0025] Preferably, the base in step (2) is an inorganic base, which is selected from ammonia, sodium hydroxide, sodium carbonate, potassium bicarbonate, sodium phosphate or potassium phosphate, preferably sodium phosphate; or an organic base, which is selected from triethylamine, N,N-diisopropylethylamine, pyridine, sodium tert-butoxide, sodium ethoxide or sodium methoxide, preferably triethylamine or sodium ethoxide.

[0026] Preferably, the pH adjustment temperature using alkali in step (2) is 20–80°C, more preferably 25–60°C.

[0027] Preferably, the pH adjusted by alkali in step (2) is 7.0 to 9.0, and more preferably 7.5 to 8.0.

[0028] Preferably, the post-processing in step (2) includes the following steps: concentration, addition of water for crystallization, cooling, filtration, washing with water, and drying to obtain crude fenelitone (IIa) product, which is further refined to obtain fine fenelitone (IIa) product; wherein, the mass-volume ratio of the fine fenelitone diastereomeric salt (III) product to the added crystallization water is 1:10-20 g / ml.

[0029] Preferably, the specific reaction steps of the present invention are as follows:

[0030] Finelone racemic (II) was reacted with D-(+)-dibenzoyl tartaric acid (IV) in a solvent, and the reaction was followed by post-treatment to prepare wet finelone diastereomeric salt (III). DMF and wet finelone diastereomeric salt (III) were added to a reactor, and the mixture was heated to dissolve. Water was then added dropwise to crystallize the solution. The mixture was cooled, filtered, washed with water, and dried to obtain purified finelone diastereomeric salt (III). Solvent and purified finelone diastereomeric salt (III) were added to a reactor, and the pH was adjusted with alkali. The mixture was concentrated, water was added to crystallize the solution, and the mixture was cooled, filtered, washed with water, and dried to obtain crude finelone (IIa). Further purification was carried out to obtain purified finelone (IIa).

[0031] Another object of the present invention is to provide a method for refining and crystallizing the intermediate phenelzine diastereomeric salt (III), wherein step (1) of the method for refining and crystallizing the intermediate phenelzine diastereomeric salt (III) includes the following steps:

[0032] The wet sample of fenelone diastereomeric salt (III) was dissolved in a solvent, water was added to crystallize it, and the refined fenelone diastereomeric salt (III) was prepared by post-treatment, which included cooling, filtration, washing and drying.

[0033] Preferably, the solvent for dissolving the wet product of the nonelinone diastereomeric salt (III) is one or two of DMF, DMA, and NMP, with DMF being preferred.

[0034] Preferably, the mass-to-volume ratio of the solvent for dissolving the racemic phenelzine (II) to the wet phenelzine diastereomer salt (III) is 1:2 to 8 g / ml, for example, 1:3.75 g / ml, 1:7.31 g / ml, or 1:4 g / ml.

[0035] Preferably, the wet dissolution temperature of the phenelzine diastereomer salt (III) is 40–80°C, more preferably 60–80°C.

[0036] Preferably, the volume ratio of the water used for crystallization to the solvent added in the purification and crystallization method of the wet product of phenelzine diastereomer salt (III) is 1 to 8:1. More preferably, the volume ratio of the water used for crystallization to the solvent added is 2 to 6:1.

[0037] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0038] 1. By improving the existing technology and process, commercially available and inexpensive D-(+)-dibenzoyl tartaric acid (Ⅳ) was used as a resolving agent, which improved the optical purity of the intermediate non-nelitone diastereomeric salt (Ⅲ).

[0039] 2. By improving the existing technology and process, the risk of residual chiral substituted tartrate ester impurities in phenelzine (IIa) has been eliminated, and no further processing is required.

[0040] 3. The preparation method of this invention has mild reaction conditions, simple operation, high product yield and purity, and low production cost, making it very suitable for industrial production. Detailed Implementation

[0041] The invention will be further described in detail below through specific embodiments, but this does not limit the scope of the invention. The phenelzine diastereomeric salt (III) before purification in this invention can be prepared by any method, and can be used in the purification process of this invention in dry or wet form, or commercially available phenelzine diastereomeric salt (III) can be used.

[0042] Example 1: Preparation of intermediate phenelzine diastereoside (III)

[0043] Add 2000 ml of 70% ethanol / water solution (V / V) and 160 g of phenelzine racemic (II) to the reactor. Add 83.3 g of D-(+)-dibenzoyl tartaric acid (IV) / 320 ml of 70% ethanol / water solution at 50°C. After the addition is complete, rinse with 80 ml of 70% ethanol / water solution, and then react at 70°C for 3 h. Cool to about 30°C and stir for 14 h. Filter, and wash the filter cake twice with 100 ml of 70% ethanol / water solution to obtain 200.05 g of wet phenelzine diastereomer salt (III) (enantiomer purity (ee): 97.38%).

[0044] The wet sample was then dissolved in 600 ml of DMF at 80°C, followed by the addition of 1200 ml of water. The mixture was stirred for 3 hours after the addition was complete. The temperature was lowered to 25°C and stirred for 1 hour. The mixture was then filtered, and the filter cake was washed twice with 160 ml of water. The product was then vacuum dried at 55°C for 8 hours to obtain 155.60 g of purified fenelone diastereomeric salt (III), with a yield of 99.9% and an enantiomeric purity (ee) of 99.80%.

[0045] Example 2: Preparation of crude fenelazolone (IIa)

[0046] Add 1500 ml of anhydrous ethanol and 750 ml of aqueous solution to the reactor. While stirring, add 150 g of fenelone diastereomeric salt (III) prepared in Example 1. Adjust the pH to 7.5 at 60°C using a 63 kg sodium phosphate / 630 ml solution. After adjustment, stir for 3 h, concentrate under reduced pressure to remove ethanol, and add 1500 ml of water dropwise. After distillation, cool to approximately 30°C and stir for 14 h. Filter, rinse with 1000 ml of water, and vacuum dry at 55°C for 9 h to obtain 73.69 g of crude fenelone (IIa), yield: 95.6%, enantiomeric purity (ee): 99.98%, D-(+)-dibenzoyl tartaric acid: not detected.

[0047] Example 3: Purification of fenelazolone (IIa)

[0048] 1155 ml of anhydrous ethanol was added to the reactor, and 55 g of phenelzine enantiomer (IIa) prepared in Example 2 was added under stirring. The mixture was dissolved and stirred at 70 °C for 1 h, then hot-filtered and washed with 55 ml of anhydrous ethanol. The mixture was concentrated under reduced pressure to a remaining volume of about 220 ml, cooled to 5 °C and stirred for 1 h, filtered, washed three times with 25 ml of anhydrous ethanol, and dried under vacuum at 60 °C for 6 h to obtain 50.80 g of purified phenelzine (IIa), yield: 92.4%, enantiomer purity (ee): 100.0%, D-(+)-dibenzoyl tartaric acid: not detected.

[0049] Example 4: Preparation of intermediate phenelzine diastereoside (III)

[0050] Add 2000 ml of 70% ethanol / water solution (V / V) and 160 g of phenelzine racemic salt (II) to the reactor. Add 83.3 g of D-(+)-dibenzoyl tartaric acid (IV) / 320 ml of 70% ethanol / water solution at 50°C. After the addition is complete, rinse with 80 ml of 70% ethanol / water solution, and then react at 70°C for 3 h. Cool to about 30°C and stir for 14 h. Filter, and wash the filter cake twice with 100 ml of 70% ethanol / water solution to obtain 195.15 g of wet phenelzine diastereomer salt (III) (enantiomer purity (ee): 96.62%).

[0051] The wet sample was dissolved in 1170 ml of DMF at 60°C, and 7000 ml of water was added dropwise. After the addition was complete, the mixture was stirred for 3 hours. The mixture was then cooled to 25°C and stirred for 1 hour. After filtration, the filter cake was washed twice with 160 ml of water and dried under vacuum at 55°C for 8 hours to obtain 154.80 g of purified fenelone diastereomeric salt (III), with a yield of 99.9% and an enantiomeric purity (ee) of 99.84%.

[0052] Example 5: Preparation of crude fenelazolone (IIa)

[0053] Add 2250 ml of anhydrous ethanol and 750 ml of aqueous solution to the reactor. While stirring, add 150 g of the fenelone diastereomeric salt (III) prepared in Example 4. Adjust the pH to 8.0 at 25°C using a 63 kg sodium phosphate / 630 ml solution. After adjustment, stir for 3 h. Concentrate under reduced pressure to remove ethanol, and add 3000 ml of water dropwise. After distillation, cool to approximately 30°C and stir for 14 h. Filter, rinse with 1000 ml of water, and vacuum dry at 55°C for 3 h to obtain 72.13 g of crude fenelone enantiomer (IIa), yield: 93.6%, enantiomer purity (ee): 99.98%, D-(+)-dibenzoyl tartaric acid: not detected.

[0054] Example 6: Purification of fenelazolone (IIa)

[0055] 1260 ml of anhydrous ethanol was added to the reactor, and 60 g of phenelzine enantiomer (IIa) prepared in Example 5 was added under stirring. The mixture was dissolved and stirred at 70 °C for 1 h, hot filtered, and washed with 60 ml of anhydrous ethanol. The mixture was concentrated under reduced pressure to a remaining volume of about 220 ml, cooled to 5 °C, stirred for 1 h, filtered, washed three times with 25 ml of anhydrous ethanol, and dried under vacuum at 60 °C for 7 h to obtain 56.02 g of purified phenelzine (IIa), yield: 93.4%, enantiomer purity (ee): 100.0%, D-(+)-dibenzoyl tartaric acid: not detected.

[0056] Example 7: Preparation of intermediate phenelzine diastereoside (III)

[0057] 116.2 kg of anhydrous ethanol and 63.1 kg of purified water were added to the reactor. While stirring, 16.15 kg of racemic phenelzine (II) was added. A mixed solution of 8.41 kg of D-(+)-dibenzoyl tartaric acid (IV) / 18.6 kg of anhydrous ethanol / 10.1 kg of purified water was added at 50°C. After the addition was complete, the mixture was rinsed with 4.6 kg of anhydrous ethanol / 2.5 kg of purified aqueous solution, and then reacted at 70°C for 3 h. The mixture was cooled to approximately 30°C and stirred for 14 h. After centrifugation, the mixture was rinsed with 15.4 kg of anhydrous ethanol / 8.3 kg of purified water to obtain 18.46 kg of wet phenelzine diastereomer salt (III) (enantiomer purity (ee): 94.92%).

[0058] The wet sample was dissolved in 61.3 kg of DMF at 77°C, and 258 kg of purified water was added continuously while stirring for 2 hours. The mixture was then cooled to 25°C and stirred for 1 hour, centrifuged, washed with 32.3 kg of purified water, and vacuum dried at 55°C for 10 hours to obtain 15.62 kg of purified fenelone diastereomeric salt (III), yield: 99.4%, enantiomeric purity (ee): 99.68%.

[0059] Example 8: Preparation of crude fenelazolone (IIa)

[0060] 122.7 kg of anhydrous ethanol and 77.8 kg of purified water were added to the reaction vessel. While stirring, 15.55 kg of phenelzine diastereomeric salt (III) prepared in Example 7 was added. The pH was adjusted to 7.9 at 45°C using a 6.48 kg sodium phosphate / 64.8 kg solution. After adjustment, the mixture was stirred for 3 hours. The ethanol was removed by vacuum concentration, and 249 kg of purified water was added. After distillation, the mixture was cooled to approximately 30°C and stirred for 7 hours. After centrifugation, the mixture was washed with 155.5 kg of purified water and dried under vacuum at 55°C for 12 hours to obtain 7.41 kg of crude phenelzine (IIa). Yield: 92.7%, enantiomeric purity (ee): 99.98%, D-(+)-dibenzoyl tartaric acid: not detected.

[0061] Example 9: Purification of fenelazolone (IIa)

[0062] 121 kg of anhydrous ethanol was added to the reaction vessel, and 7.3 kg of phenelzine enantiomer (IIa) prepared in Example 8 was added and washed with 5.8 kg of anhydrous ethanol. The mixture was concentrated under reduced pressure to a remaining volume of about 30 L, cooled to 5 °C and stirred for 1 h, centrifuged, washed with 5.3 kg of anhydrous ethanol, and dried under vacuum at 60 °C for 12 h to obtain 6.57 kg of purified phenelzine (IIa), yield: 90.0%, enantiomer purity (ee): 100.0%, D-(+)-dibenzoyl tartaric acid: not detected.

Claims

1. A method for preparing phenelzine from a racemic mixture, characterized in that, The preparation method includes the following steps: (1) The racemic phenelzine (II) was reacted with D-(+)-dibenzoyl tartaric acid (IV) in a solvent to prepare the intermediate phenelzine diastereomeric salt (III) wet product, and then purified and crystallized to obtain the refined phenelzine diastereomeric salt (III); (2) The intermediate phenelzine diastereomeric salt (III) was prepared into phenelzine (IIa) by alkali release, pH adjustment and post-treatment in a solvent; Its synthetic route is as follows:

2. The method for preparing phenelzine from a racemic mixture of phenelzine according to claim 1, characterized in that, The molar ratio of compound II to compound IV in step (1) is 1:0.5 to 1, preferably 1:0.5 to 0.65, and the reaction solvent for compound II and compound IV is a mixture of ethanol and water.

3. The method for preparing phenelzine from a racemic mixture of phenelzine according to claim 1, characterized in that, In step (1), the purification and crystallization method of the intermediate diastereomeric salt (III) includes the following steps: dissolving the wet product of diastereomeric salt (III) in a solvent, adding water to crystallize, and preparing the product of diastereomeric salt (III) by post-treatment.

4. The method for preparing phenelzine from the racemic mixture of phenelzine according to claim 3, characterized in that, The solvent for dissolving the wet product of the non-nelitone diastereomeric salt (III) is one or two of DMF, DMA, and NMP, with DMF being preferred.

5. The method for preparing phenelzine from the racemic mixture of phenelzine according to claim 3, characterized in that, The mass-to-volume ratio of the solvent for dissolving the racemic phenelzine (II) to the wet phenelzine diastereomer salt (III) is 1:2 to 8 g / ml, for example, 1:3.75 g / ml, 1:7.31 g / ml, or 1:4 g / ml.

6. The method for preparing phenelzine from the racemic mixture of phenelzine according to claim 3, characterized in that, The wet dissolution temperature of the phenelzine diastereomer salt (III) is 40–80°C, preferably 60–80°C.

7. The method for preparing phenelzine from the racemic mixture of phenelzine according to claim 3, characterized in that, The purification and crystallization method for the wet product of phenelzine diastereomer salt (III) involves adding crystallization water in a volume ratio of 1 to 8:1, and more preferably, the volume ratio of crystallization water to dissolving solvent is 2 to 6:1; the post-treatment includes cooling, filtration, washing, and drying.

8. The method for preparing phenelzine from the racemic mixture of phenelzine according to claim 1, characterized in that, The solvent mentioned in step (2) is N,N-dimethylformamide, N,N-dimethylacetamide, methanol and water, ethanol and water, or acetonitrile and water, preferably a combination of ethanol and water, wherein the volume ratio of ethanol to water is 2 to 3:1; the base is an inorganic base, wherein the inorganic base is selected from ammonia, sodium hydroxide, sodium carbonate, potassium bicarbonate, sodium phosphate or potassium phosphate, preferably sodium phosphate; or an organic base, wherein the organic base is selected from triethylamine, N,N-diisopropylethylamine, pyridine, sodium tert-butoxide, sodium ethoxide or sodium methoxide, preferably triethylamine or sodium ethoxide.

9. The method for preparing phenelzine from the racemic mixture of phenelzine according to claim 1, characterized in that, In step (2), the pH is adjusted using an alkali at a temperature of 20–80°C, preferably 25–60°C; the pH adjusted by the alkali is 7.0–9.0, preferably 7.5–8.0; the post-processing includes the following steps: concentration, addition of water for crystallization, cooling, filtration, washing with water, and drying to obtain crude fenelone (IIa), which is further refined to obtain high-quality fenelone (IIa).

10. The method for preparing phenelzine from the racemic mixture of phenelzine according to claim 9, characterized in that, The mass-to-volume ratio of the refined phenelzine diastereomer salt (III) to the added crystallization water is 1:10-20 g / ml.

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