Process for the preparation of a non-naloxone intermediate and its diastereomeric salts

Abstract

This invention relates to a method for preparing the fenelone intermediate 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxylic acid ester, and also relates to diastereomeric salts (Va), (Vb), (Vc), and / or (Vd). This method is simple to operate, and the diastereomeric salts can be obtained with very high chemical and enantiomeric purity (tartrate ester content <0.05%) through a single dissociation, avoiding the raw material loss and waste problems caused by multiple dissociations. It also has low production costs and meets the requirements of green production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a method for preparing the nonelinone intermediate 2-cyanoethyl(4S)-4-(4-cyano-2-methoxyphenyl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxylic acid ester and its diastereomeric salts (Va), (Vb), (Vc) and / or (Vd). Background Technology

[0002] Finelinone, chemical name: (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide, has the structure shown in formula (Ia):

[0003]

[0004] Compound (I) is a racemic mixture of phenelzine. The enantiomers of compound (I) involve phenelzine (or "compound (Ia)") and compound (Ib), with the structures shown below:

[0005]

[0006] Fennellone (Ia) is 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. Compounds of formula (I) or (Ia) and methods for their preparation are described in WO2008104306A3, ChemMedChem2012,7,1385, and WO2016016287A1.

[0007] Since only the enantiomer of compound (Ia) has pharmacological activity, in order to obtain optically pure compound (Ia), compound (I) must be separated into enantiomers (Ia) and (Ib).

[0008] Patent CN112041318A describes a method for resolving compounds of formula (I) by using chiral substituted tartrate esters of general formula (IIIa) or (IIIb) to resolve compounds of formula (I) into (Ia) and / or (Ib).

[0009]

[0010] However, this patent only describes the use of D-benzoyl tartaric acid as a resolving agent, with an actual target isomer recovery rate of approximately 90%, resulting in significant resolving losses. Furthermore, according to the specification of patent CN112041318A, the step of treating the diastereomer salt with alkali typically requires multiple dissociations to reduce the chiral substituted tartaric acid ester content of the resolving agent to below 0.15%. Additionally, theoretically, half of the enantiomers participate in the reaction during the synthetic steps prior to obtaining the racemic mixture of formula (I), and these half of the enantiomers do not transform into the compound of formula (Ia). Although this method resolves the compound of formula (I) to obtain the compound of formula (Ia), it consumes a large amount of raw materials, reagents, and solvents, resulting in poor atom economy and high production costs.

[0011] Patents WO2021074072A1 and CN114667284A describe a method for resolving the racemic mixture of compound (IV) by using (2R,3R)-2,3-bis(4-nitrobenzoyl)tartaric acid as a resolving agent, and then obtaining phenelzine by alkaline hydrolysis, alkylation, hydrolysis and ammonolysis of the diastereomer salt.

[0012]

[0013] The method yielded intermediate diastereomeric salts with an ee value of less than 85%, which only increased to 98% after further purification. The overall resolution yield was less than 40%, and the resolving reagent (2R,3R)-2,3-bis(4-nitrobenzoyl)tartaric acid was expensive, difficult to obtain, and costly, which was not conducive to industrialization.

[0014] Patent CN116715664A describes another method for resolving compound (IV) using D-camphor sulfonic acid. Although this method achieves a purity (ee value) of 98% for the diastereomeric salt of the intermediate, it still falls short of the ee value exceeding 99%, and the highest yield is only 45%, resulting in significant raw material loss. Furthermore, the solvent system used is complex, and the resolving agent is expensive, increasing the costs of solvent and resolving agent usage, as well as solvent recovery, which is detrimental to industrial production. Another point of concern is the use of alcohol solvents during resolution, which may react with sulfonic acid substances to generate genotoxic impurities, increasing the risk of exceeding genotoxic impurity limits in phenelzine products. Summary of the Invention

[0015] To address the shortcomings of existing technologies, this invention provides a method for preparing 2-cyanoethyl(4S)-4-(4-cyano-2-methoxyphenyl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxylic acid ester using chiral substituted tartrates of formula (IIIa) or (IIIb) as resolving agents. This method is simple to operate, and the resulting product has very high chemical and enantiomeric purity (tartrate content <0.05%), avoiding raw material loss and waste issues caused by multiple dissociations. It also has low production costs and meets the requirements of green production.

[0016] This invention provides a method for preparing compounds of formula (IVa) and / or formula (IVb), characterized in that a chiral substituted tartrate ester of formula (IIIa) or (IIIb) is used as a resolving agent to resolve the racemic mixture of formula (IV).

[0017]

[0018] Where Ar is selected from one of the following formulas:

[0019]

[0020]

[0021] The asterisk (*) represents a connection point.

[0022] Preferably, the above method includes: step S1. The racemic mixture of formula (IV) reacts with a chiral substituted tartrate ester of formula (IIIa) or (IIIb) to generate diastereomeric salts (Va), (Vb), (Vc) and / or (Vd),

[0023]

[0024] The definition of Ar is the same as above.

[0025] Specifically, the preparation of the diastereomeric salts shown in formulas (Va), (Vb), (Vc), and (Vd) is carried out as follows:

[0026]

[0027] The reaction of the racemic mixture of formula (IV) with the chiral substituted tartrate of formula (IIIa) or (IIIb) results in four choices for the formation of diastereomeric salts (Va, Vb, Vc, and Vd). When the racemic mixture of formula (IV) reacts with the chiral substituted tartrate of formula (IIIa), the enantiomer with the S configuration preferentially participates in salt formation, yielding the diastereomeric salt of formula (Va). The diastereomeric salt of formula (Va) precipitates almost quantitatively from solution and can then be separated from solution by filtration, while the diastereomeric salt of formula (Vd) formed by the enantiomer with the R configuration and the chiral substituted tartrate of formula (IIIa) remains in the mother liquor. Further concentration and purification of the mother liquor yields the diastereomeric salt of formula (Vd). When the racemic mixture of formula (IV) reacts with the chiral substituted tartrate of formula (IIIb), the enantiomer with the R configuration preferentially participates in salt formation, yielding the diastereomeric salt of formula (Vb). The diastereomeric salt of formula (Vb) can be precipitated almost quantitatively from solution and then separated by filtration, while the diastereomeric salt of formula (Vc) formed by the S-configuration enantiomer and the chiral substituted tartrate of formula (IIIb) remains in the mother liquor. Further concentration and purification of the mother liquor yields the diastereomeric salt of formula (Vc).

[0028] The stoichiometric ratio of compound (IV) to compound (IIIa) or (IIIb) and the choice of solvent can be used to optimize yield and enantiomeric purity.

[0029] Finelone (Ia) has an S configuration. Tartrate esters with the S,S-configuration are preferred for racemic resolution because, in this case, diastereomeric salts of the S-enantiomer are preferably formed.

[0030] The amount of tartrate ester of formula (IIIa) or formula (IIIb) is 0.5 to 3.0 equivalents of the amount of compound of formula (IV), preferably 0.5 to 1.5 equivalents, more preferably 0.5 to 1.0 equivalents, and most preferably 0.55 equivalents.

[0031] Diastereic salts are formed in water or organic solvents or solvent mixtures consisting of water and organic solvents.

[0032] In this application, examples of suitable organic solvents include water, ethanol, methanol, isopropanol, n-propanol, dichloromethane, tetrahydrofuran, acetonitrile, methyl tert-butyl ether, or acetone. Additionally, the following solvents have been used: methanol / water 2:1; methanol / acetonitrile 1:1; isopropanol / water 3:1; tetrahydrofuran / water 2:1; and acetonitrile / water 3:2. The solvent ratio refers to the volume-to-volume ratio (v / v). For example, a solvent mixture of methanol / water 2:1 contains 40 mL of methanol and 20 mL of water. Therefore, the volume is based on the total volume of the solvent.

[0033] Preferably, the formation of the diastereomeric salt is carried out in an ethanol / water solvent mixture, wherein the ethanol:water ratio is in the range of 1 to 9:1 (v / v), preferably 3 to 9:1 (v / v), and particularly preferably 3:1 (v / v). The solvent mixture can be prepared in advance or in situ after all components are loaded into a container. The solvent mixture can be used in excess of 4 to 40 times, based on the mass of the compound of formula (IV), i.e., 4 to 40 L of solvent mixture is used per 1 kg of compound of formula (IV), preferably 6 to 12 times excess.

[0034] The specific process for preparing diastereomeric salts is as follows:

[0035] Reaction stage: First, compound (IV) is added to the solvent mixture at room temperature, then heated to 0–78°C, but preferably 70–78°C, and stirred until dissolved. Then, compound (IIIa) or (IIIb) is added to the above system, and stirred at 70–78°C for 0.5–3.5 hours, preferably 0.5–1.5 hours.

[0036] Crystallization stage: The reaction system is cooled to 0-30°C, preferably 15-25°C, over 2-16 hours, preferably 3-5 hours. Thereafter, stirring is continued at 15-25°C for 12-24 hours, preferably 12-18 hours, and most preferably 12-14 hours.

[0037] Separation stage: Separation of diastereomer salts (Va), (Vb), (Vc) and / or (Vd).

[0038] This invention involves adding the racemic mixture to a mixed solvent, heating it to dissolve it, then adding a resolving agent to obtain a homogeneous system. The system is then stirred to crystallize and resolve the mixture. The optimized order of adding the ingredients ensures sufficient salt formation, thereby greatly shortening the crystallization time.

[0039] Separation is performed using methods known to those skilled in the art, such as by filtration or centrifugation. The filter cake obtained in this manner can be washed once or several times with a solvent or a mixture of solvents. It is then dried under reduced pressure at a temperature of 45–65°C, preferably 45–50°C. The diastereomeric salts do not necessarily need to be dried, but can also be used wet in the next processing stage.

[0040] Using the above steps, diastereomeric salts with very high chemical purity can be prepared, and the enantiomeric excess value of the obtained diastereomeric salts is usually >99.0%.

[0041] The method for preparing compounds of formula (IVa) and / or formula (IVb) further includes step S2: treating the diastereomeric salts of formulas (Va), (Vb), (Vc) and / or (Vd) with a base.

[0042] To prepare chiral compounds (IVa) or (IVb), the diastereomeric salts of formulas (Va), (Vb), (Vc), or (Vd) must be treated with a base.

[0043]

[0044]

[0045] In the above-mentioned preparative compounds of formula (IVa) or (IVb), a suitable base is an inorganic base or an organic base.

[0046] For inorganic bases, ammonia, sodium hydroxide, lithium hydroxide, potassium hydroxide, ammonium carbonate, sodium carbonate, potassium carbonate, lithium carbonate, ammonium bicarbonate, sodium bicarbonate, potassium bicarbonate, ammonium phosphate, sodium phosphate, or potassium phosphate can be used, with sodium hydroxide, sodium phosphate, or potassium phosphate being preferred, and sodium hydroxide being the most preferred. The inorganic base can be used in anhydrous form or as a hydrate, for example, sodium hydroxide or sodium hydroxide monohydrate can be used. The amount of inorganic base used is such that the pH of the reaction system is controlled between 6.7 and 9.5, preferably between 7.1 and 8.0, and most preferably 7.5. This can be achieved by using a pH meter installed in the reactor to control, adjust, and gradually meter the addition of the base.

[0047] For organic bases, aliphatic or aromatic bases can be used, such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, propylamine, isopropylamine, 1,3-propanediamine, 1,2-propanediamine, tripropylamine, cyclohexylamine, dicyclohexylamine, N,N-diisopropylethylamine, aniline, diphenylamine, triphenylamine, monoethanolamine, diethanolamine, triethanolamine, N-methylmorpholine, pyridine, sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, or sodium methoxide, preferably triethylamine, N-methylmorpholine, N,N-diisopropylethylamine, or aniline. The molar ratio of the organic base to formula (Va), (Vb), (Vc), or (Vd) is 1.0 to 6.5:1.

[0048] Compounds of formula (IVa) or (IVb) are released in water or a water-soluble organic solvent (such as ethanol, isopropanol, methanol, or acetone) or a mixture of water and a water-soluble organic solvent (such as ethanol, isopropanol, methanol, or acetone). The use of a mixture of water and ethanol has been found advantageous, wherein the solvent mixing ratio is ethanol:water = 1:3 to 25 (v / v), preferably a mixture of ethanol:water = 1:20 (v / v). The solvent mixture can be prepared in advance or in situ after all components are loaded into a container. The amount of the solvent mixture can be 5 to 40 times the mass of the diastereomeric salt (Va, Vb, Vc, or Vd) used; for example, 5 to 40 L of solvent mixture is used for 1 kg of diastereomeric salt, preferably 18 to 35 times, more preferably 28 to 35 times, and most preferably 33 times.

[0049] Compounds of formula (IVa) or (IVb) are released through the following steps:

[0050] First, the diastereomeric salt (Va, Vb, Vc, or Vd) is added to the solvent at a temperature of 2°C to 80°C, preferably 20°C to 60°C, followed by the addition of the base. The base can be added very rapidly (within minutes) or very slowly (within hours), for example, from 3 minutes to up to 2 hours. In any case, a faster addition is preferred, such as metered addition within 3 to 30 minutes. It is advantageous to control the reaction system at a temperature of 10°C to 78°C, preferably 20°C to 60°C, and most preferably 45°C to 55°C, with continuous stirring. The continuous stirring time can be 1 to 24 hours, preferably 2 to 6 hours, more preferably 2 to 3 hours. The mixture is then cooled to 20°C to 30°C, and then stirred again for 1 to 35 hours, preferably 3 to 24 hours, more preferably 10 to 16 hours.

[0051] The separation of formula (IVa) or (IVb) compounds can be carried out by methods known to those skilled in the art, such as by filtration or centrifugation. The resulting filter cake can be washed once or several times with the reaction solvent. It is then dried under reduced pressure (preferably <100 mbar) at a temperature in the range of 50–80°C, preferably 50°C.

[0052] Using the above steps, crude products of formula (IVa) or formula (IVb) with very high chemical purity can be prepared. The enantiomeric excess of the crude product is typically >98%, preferably >99%; the content of the resolving agent tartrate ester is <0.05%.

[0053] Compounds of formula (IVa) or (IVb) can be further alkylated, hydrolyzed, or ammonolyzed to obtain fenelone of formula (Ia) or its enantiomer of formula (Ib), as shown below:

[0054]

[0055] Another aspect of the present invention provides a method for preparing a compound of formula (IVa) by using a chiral substituted tartrate ester of formula (IIIa) as a resolving agent to resolve the racemic mixture of formula (IV) to obtain 2-cyanoethyl(4S)-4-(4-cyano-2-methoxyphenyl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxylic acid ester of formula (IVa).

[0056]

[0057] The definition of Ar is the same as above.

[0058] Preferably, especially for industrial-scale implementation, the chiral substituted tartrate of formula (IIIa) is D-di-o-methylbenzoyl tartaric acid, with the structure shown in formula (IIIa'):

[0059]

[0060] In the above method for preparing compound (IVa), the racemic mixture of formula (IV) reacts with D-di-o-methylbenzoyl tartaric acid of formula (IIIa').

[0061]

[0062] The reaction in an ethanol / water binary solvent system yields a diastereomeric salt of formula (Va').

[0063]

[0064] Subsequently, in an ethanol / water binary solvent system, an aqueous sodium hydroxide solution was used to dissociate the diastereomeric salt of formula (Va') to obtain 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxylic acid ester of formula (IVa).

[0065]

[0066] Another aspect of the present invention provides a diastereomeric salt with the structure shown in formulas (Va), (Vb), (Vc), or (Vd):

[0067]

[0068] Where Ar is selected from one of the following formulas:

[0069]

[0070] The asterisk (*) represents a connection point.

[0071] Preferably, the structure of the above-mentioned diastereomeric salt is shown in the following formula (Va'):

[0072]

[0073] Another aspect of the present invention provides a method for preparing phenelzine as shown in formula (Ia).

[0074] The steps include (1), (2), (3), (4), and (5):

[0075] (1) Compound of formula (IV)

[0076]

[0077] Reaction with tartrate esters of formula (IIIa) or (IIIb)

[0078]

[0079] Ar is defined as above, and is a diastereomeric salt of the formula (Va) or (Vc).

[0080]

[0081] (2) Treat the diastereomeric salt of formula (Va) or (Vc) obtained in step (1) with an alkali to obtain a compound of formula (IVa).

[0082]

[0083] (3) Under acidic catalysis, the compound of formula (IVa) obtained in step (2) is reacted with triethyl orthoacetate to obtain compound of formula (VIa).

[0084]

[0085] (4) Hydrolyze the compound of formula (VIa) obtained in step (3) to obtain the compound of formula (VIIa).

[0086]

[0087] (5) In tetrahydrofuran solvent, without a catalyst or with a catalytic amount of 4-(dimethylamino)pyridine, the compound of formula (VIIa) obtained in step (4) is reacted with N,N-carbonyldiimidazole, then hexamethyldisilazane is added, and the mixture is heated at 60-70°C for 15-24 hours. Then, a tetrahydrofuran / water binary solvent is added to obtain formula (Ia).

[0088] Compounds.

[0089] The specific process of step (5) is as follows: In tetrahydrofuran, at a temperature of 20-50°C (it has been found that a preferred method is to start at 20°C, then stir at that temperature for 1-2 hours, and then continue stirring at 50°C for 2-3 hours), compound (VIIa) reacts with 1,1'-carbodiimidazole (CDI) to obtain onium-based imidazolide, thereby activating the carboxyl group. The molar ratio of CDI to compound (VIIa) is 1.1-4.0:1, preferably 2.5-3.0:1. This reaction can be carried out without the addition of a catalyst, or under the catalysis of 4-dimethylaminopyridine (DMAP), with the amount of DMAP being 5-15 mol% of the amount of compound (VIIa), preferably 15 mol%.

[0090] After activation, add 3-8 equivalents, preferably 4.0 equivalents, of hexamethyldisilazane, and heat the mixture under reflux for 16-24 hours, preferably 16 hours, to continue the reaction. After the reaction is complete, cool the reaction mixture to 0-3°C and meterly add water or a mixture of water / tetrahydrofuran. It has been found advantageous to use 0.5 to 0.7 times the amount of reactant of formula (VIIa), and particularly advantageous to use 0.52 times the amount of water, i.e., 0.52 L of water for 1 kg of reactant of formula (VIIa). Water can be added directly. After the addition is complete, heat the mixture to reflux for a total of 1-3 hours, preferably 1 hour. Concentrate the reaction solution to dryness, add ethanol / water in a 1:2 (v / v) ratio, stir for 1 hour, then cool to 0-10°C and stir further at this temperature for 2-3 hours, preferably 2 hours. Subsequently, separate the product by filtration or centrifugation. Wash the product with water and dry it under vacuum at a temperature of 30°C-90°C, preferably 40°C-70°C. After drying, the compound of formula (Ia) is obtained, with a product yield typically greater than 80% and a purity typically >98% (HPLC).

[0091]

[0092] In step (1) above, the diastereomeric salts of formula (Va) or (Vc) can be separated by filtration. Then, an alkali is added to the mother liquor containing other diastereomeric salts (compounds of formula (Vb) or (Vd)) to adjust the pH of the mother liquor to >7, preferably pH = 7.5. The alkali is ammonia, sodium hydroxide, lithium hydroxide, potassium hydroxide, ammonium carbonate, sodium carbonate, potassium carbonate, lithium carbonate, ammonium bicarbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, or ammonium phosphate. Sodium hydroxide, sodium phosphate, or potassium phosphate is preferred, and sodium hydroxide is particularly preferred. The organic solvent is then distilled off under normal or reduced pressure, and the mother liquor is concentrated to precipitate compound (IVb). The precipitate is filtered off, washed with a suitable amount of solvent, and dried. The obtained compound (IVb) can be further alkylated, hydrolyzed, and ammonolyzed to obtain compound (Ib).

[0093] The beneficial effects of this invention are as follows: The racemic mixture is first heated to dissolve in a solvent mixture, then a resolving agent is added to obtain a homogeneous system. The mixture is then stirred to crystallize and dissolve the salt. This optimized feeding sequence ensures sufficient salt formation, thus significantly shortening the crystallization time. Furthermore, in the alkaline dissociation step, the diastereomeric salt of this invention can be dissociated in a single step to obtain a crude product with very high chemical and enantiomeric purity. The tartrate ester content of the resolving agent is <0.05%, avoiding the raw material loss and waste problems caused by multiple dissociations, greatly reducing production costs and meeting the requirements of green production. Detailed Implementation

[0094] Reference will now be made to detailed embodiments of the present invention, one or more of which are described below. Each example is provided for explanation and not for limitation of the invention. In fact, it will be apparent to those skilled in the art that various modifications and variations can be made to the invention without departing from its scope or spirit. For example, features described or illustrated as part of one embodiment may be used in another embodiment to produce further embodiments.

[0095] The embodiments of this application will be described in detail below with reference to examples. Unless otherwise specified, the raw materials used in the following examples are all commercially available products.

[0096] The following reagent abbreviations and acronyms are used in this invention:

[0097] EtOH: Ethanol

[0098] DMSO: Dimethyl sulfoxide

[0099] DMAc: N,N-dimethylacetamide

[0100] DMAP: 4-Dimethylaminopyridine

[0101] THF: Tetrahydrofuran

[0102] H2O: water

[0103] CDI: N,N-carbonyldiimidazole

[0104] HMDS: Hexamethyldisilazane

[0105] 1 H-NMR: 1H NMR spectrum

[0106] HPLC: High Performance Liquid Chromatography

[0107] Ph: Benzene ring

[0108] Example 1: Preparation of diastereomeric salt (Va') using D-di-o-methylbenzoyl tartaric acid

[0109]

[0110] 10 g (0.02473 mol) of compound (IV) was suspended in a mixture of 75 mL ethanol and 25 mL water and heated to 73 °C with stirring until dissolved. 5.26 g (0.01360 mol) of D-di-o-methylbenzoyl tartaric acid was added using a solid glass funnel, and crystallization was carried out at 73 °C with stirring for 1.0 h. The mixture was then cooled to 20 °C over 3 h and stirred at this temperature for 12 h. The mixture was filtered, the filter cake was washed twice with 20 mL ethanol / water (3:1, v / v), and the product was dried under reduced pressure at 50 °C to give 9.8 g (100.2% of theoretical value) of off-white crystalline powder with an enantiomeric purity (ee value): 99.3%.

[0111] Examples 2-9 show the preparation of different diastereomeric salts using different diastereotartaric acid esters.

[0112] Using the same method as in Example 1, different types of diastereotartrate esters were changed to prepare different diastereosal salts, and the reaction results are shown in Table 1 below.

[0113] Table 1

[0114]

[0115]

[0116] Example 10 Preparation of compound (IVa)

[0117] Nine g of the compound of formula (Va') prepared in Example 1 was suspended in a mixture of 14 mL of ethanol and 280 mL of water. Subsequently, an aqueous sodium hydroxide solution (100 g of sodium hydroxide dissolved in 1000 mL of water) was added linearly and uniformly over 1 hour, and the pH was adjusted to pH = 7.5. The mixture was heated to an internal temperature of 50 °C over 1 hour and stirred at this temperature for 3.0 hours. The mixture was then cooled to 25 °C over 1 hour and stirred at this temperature for another 1 hour. The mixture was filtered, the filter cake was washed twice with 20 mL of ethanol / water (1:20, v / v), and the product was dried under reduced pressure at 50 °C to give 4.5 g (98.0% of the theoretical value) of an off-white crystalline powder with an enantiomeric purity (ee value) of 99.4% and a D-di-o-methylbenzoyl tartaric acid content of 0.03%.

[0118] Preparation of compounds of formula (IVa) in Examples 11-18

[0119] Using the same method as in Example 10, with other conditions remaining unchanged, only the type and amount of alkali were changed, and the reaction was considered. The results are shown in Table 2 below.

[0120] Table 2

[0121]

[0122] Preparation of compound formula (VIa) in Example 19

[0123]

[0124] Under nitrogen protection, 2248g of DMAc, 400g of compound (IVa), 400g of triethyl orthoacetate, and 1g of 98% concentrated sulfuric acid were added sequentially to the reactor. The external temperature of the reactor was set to 130-140℃, and the internal temperature was controlled at 110-120℃ for 2 hours. After the reaction was completed, the internal temperature of the reaction solution was lowered to 45-55℃, and 2400g of purified water was added dropwise. After the addition was complete, the mixture was stirred at the internal temperature of 45-55℃ to induce crystallization for 4-5 hours. The internal temperature was then lowered to 0-10℃ and maintained at 0-10℃ for 2 hours to induce crystallization. Centrifuge, rinse the reaction vessel with 800g of purified water, centrifuge the rinsing liquid, and vacuum dry the filter cake at 60℃ for 16 hours to obtain 393.5g (92.0% of the theoretical value) of off-white crystalline powder. The purity of compound (VIa) is 99.3%, the enantiomeric purity (ee value) is 100%, and the content of D-di-o-methylbenzoyl tartaric acid is not detected.

[0125] Example 20 Preparation of compound (VIIa)

[0126]

[0127] Under nitrogen protection, 1668.7 g of tetrahydrofuran, 312.5 g of compound (VIa), and 937.5 g of purified water were added sequentially to the reactor, and stirred until dissolved. The mixture was cooled to an internal temperature of 0-10°C and maintained at this temperature. Sodium hydroxide aqueous solution (56.3 g of sodium hydroxide dissolved in 781.3 g of purified water) was added dropwise. After the addition was complete, the reaction was carried out at an internal temperature of 0-10°C for 1 hour. After the reaction was complete, 1562.5 g of methyl tert-butyl ether was added while maintaining the internal temperature at 0-10°C. The mixture was stirred for 15-30 minutes, allowed to stand for 15-30 minutes, and then separated, collecting the aqueous phase. At 0-10°C, 937.5 g of ethyl acetate was added to the aqueous phase. The mixture was stirred for 15-30 minutes, allowed to stand for 15-30 minutes, and then separated, collecting the aqueous phase. Maintain the internal temperature at 0-10℃, add hydrochloric acid solution (68.8g of 36% concentrated hydrochloric acid dissolved in 237.5g of purified water) to the aqueous phase, and adjust the pH of the system to 6-7. After adjustment, maintain the internal temperature at 0-10℃ for crystallization for 2 hours. Centrifuge, rinse the reaction vessel with 312.5g of purified water, centrifuge the rinsing solution, wash the filter cake with 493.8g of acetonitrile, and centrifuge. Dry the filter cake under vacuum at 50℃ for 24 hours to obtain 253.6g (92.5% of the theoretical value) of off-white crystalline powder. The purity of compound (VIIa) is 99.0%, the enantiomeric purity (ee value) is 100%, and the content of D-di-o-methylbenzoyl tartaric acid is not detected.

[0128] Example 21 Preparation of compound (Ia)

[0129]

[0130] Under nitrogen protection, 1777.8 g of tetrahydrofuran, 250 g of compound (VIIa), 170.8 g of CDI, and 7975 g of 4-dimethylaminopyridine were added sequentially to the reactor, and stirred for 0.5 hours at an internal temperature of 20-30°C. The temperature was then raised to 50-60°C and maintained at 50-60°C for 3 hours. After the reaction was complete, 372.2 g of hexamethyldisilazane was added, and the temperature was raised to 60-70°C. The reaction was maintained at 60-70°C for 20 hours. After the reaction was complete, the temperature was lowered to 0-10°C, and 125 g of purified water was added dropwise while maintaining the internal temperature at 0-10°C. After the addition was complete, the internal temperature was raised to 60-70°C and maintained at 60-70°C with stirring for 2 hours. The internal temperature was then lowered to 0-10°C and maintained at 0-10°C with stirring to induce crystallization for 2 hours. Centrifuge, rinse the reaction vessel with a mixed solvent of 222.2 g tetrahydrofuran and 500 g purified water, centrifuge the rinsing solution, combine the filter cakes, and vacuum dry the filter cakes at 80 °C for 36 hours to obtain 224.4 g (90.0% of the theoretical value) of off-white crystalline powder. The purity of the crude product of formula (Ia) is 99.2%, the enantiomeric purity (ee value) is 100%, and the content of D-di-o-methylbenzoyl tartaric acid is not detected.

[0131] Under nitrogen protection, 3471.1 g of anhydrous ethanol and 220.0 g of crude compound (Ia) were added sequentially to the reactor, and the mixture was stirred. The temperature was raised to 75-80℃, and the mixture was stirred for 1-2 hours until it was basically dissolved. The mixture was filtered through a 0.45 μm filter while hot and transferred to a reactor in a clean area. The filtrate was distilled at 95-105℃ under normal pressure to a volume of 3.5V-4.5V (based on the amount of crude compound (Ia) added). After distillation, the system was cooled to 25-30℃ and kept at this temperature for 2 hours to allow crystals to precipitate. The temperature was then further lowered to 0-10℃ and kept at this temperature for 2 hours to allow crystals to precipitate again. The mixture was centrifuged, and the reactor was rinsed with 171.1 g of anhydrous ethanol. The rinsing solution was then centrifuged. The filter cakes were combined and dried under vacuum at 70℃ for 16 hours. 203.1 g (92.3% of the theoretical value) of off-white crystalline powder was obtained.

[0132] The analysis results are shown in Table 3 below.

[0133] Table 3

[0134]

[0135] Comparative Example 1

[0136] The resolution effects of (2R,3R)-2,3-bis(4-nitrobenzoyl)tartaric acid and D-camphorsulfonic acid disclosed in Example 1, CN114667284B and CN116715664A were compared, and the enantiomeric purity (ee value) of the corresponding diastereomeric salts was measured and summarized in Table 3.

[0137] Table 3

[0138] Dissolving agent Enantiomeric purity (ee value) of diastereomeric salts D-di-o-methylbenzoyl tartaric acid 99.3％ (2R,3R)-2,3-bis(4-nitrobenzoyl)tartaric acid 86.1％ D-Camphorsulfonic acid Uncrystallized

[0139] As shown in the table above, compared with the resolving agents disclosed in patents CN114667284B and CN116715664A, the resolving agent of the present invention has the best resolving effect on compound (IV).

[0140] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A method for preparing compounds of formula (IVa) and / or formula (IVb), characterized in that, Using chiral substituted tartrate esters of formula (IIIa) or (IIIb) as resolving agents, the racemic mixture of formula (IV) is resolved. Where Ar is selected from one of the following formulas: The asterisk (*) represents a connection point.

2. The method according to claim 1, characterized in that, include: Step S1. The racemic mixture of formula (IV) reacts with a chiral substituted tartrate ester of formula (IIIa) or (IIIb) to generate diastereomeric salts (Va), (Vb), (Vc) and / or (Vd). The definition of Ar is equivalent to weight 1.

3. The method according to claim 2, characterized in that, include: Separate diastereomer salts (Va), (Vb), (Vc) and / or (Vd).

4. The method according to claim 2, characterized in that, The reaction is carried out in an ethanol / water binary solvent system.

5. The method according to claim 2, characterized in that, The reaction is carried out in the temperature range of 0–78°C.

6. The method according to claim 2, characterized in that, include: Step S2. Treat the diastereomeric salts represented by formulas (Va), (Vb), (Vc) and / or (Vd) with alkali.

7. The method according to claim 6, characterized in that, The alkali is an inorganic alkali, selected from ammonia, sodium hydroxide, lithium hydroxide, potassium hydroxide, ammonium carbonate, sodium carbonate, potassium carbonate, lithium carbonate, ammonium bicarbonate, sodium bicarbonate, potassium bicarbonate, ammonium phosphate, sodium phosphate, or potassium phosphate.

8. The method according to claim 6, characterized in that, The base is an organic base, selected from methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, propylamine, isopropylamine, 1,3-propanediamine, 1,2-propanediamine, tripropylamine, cyclohexylamine, dicyclohexylamine, N,N-diisopropylethylamine, aniline, diphenylamine, triphenylamine, monoethanolamine, diethanolamine, triethanolamine, N-methylmorpholine, pyridine, sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, or sodium methoxide.

9. The method according to claim 1, characterized in that, Using a chiral substituted tartrate ester of formula (IIIa) as a resolving agent, the racemic mixture of formula (IV) was resolved to yield 2-cyanoethyl(4S)-4-(4-cyano-2-methoxyphenyl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxylic acid ester of formula (IVa). The definition of Ar is equivalent to weight 1.

10. The method according to claim 9, characterized in that, The chiral substituted tartrate of formula (IIIa) is D-di-o-methylbenzoyl tartaric acid, with the structure shown in formula (IIIa'):

11. The method according to claim 10, characterized in that, The racemic mixture of formula (IV) and the D-di-o-methylbenzoyl tartaric acid of formula (IIIa') The reaction in an ethanol / water binary solvent system yields a diastereomeric salt of formula (Va'). Subsequently, in an ethanol / water binary solvent system, an aqueous sodium hydroxide solution was used to dissociate the diastereomeric salt of formulation (Va') to obtain 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxylic acid ester (IVa).

12. A diastereomeric salt having a structure as shown in formulas (Va), (Vb), (Vc), or (Vd), Where Ar is selected from one of the following formulas: The asterisk (*) represents a connection point.

13. The diastereomeric salt according to claim 12, characterized in that, Its structure is shown in the following equation (Va').

14. A method for preparing phenelzine as shown in formula (Ia), Its features are, The steps include (1), (2), (3), (4), and (5): (1) Compound of formula (IV) Reaction with tartrate esters of formula (IIIa) or (IIIb) Where Ar is defined in the same way as in weight 1, and is a diastereomeric salt of the genera (Va) or (Vc). (2) Treat the diastereomeric salt of formula (Va) or (Vc) obtained in step (1) with an alkali to obtain a compound of formula (IVa). (3) Under acidic catalysis, the compound of formula (IVa) obtained in step (2) is reacted with triethyl orthoacetate to obtain compound of formula (VIa). (4) Hydrolyze the compound of formula (VIa) obtained in step (3) to obtain the compound of formula (VIIa). (5) In tetrahydrofuran solvent, without the addition of a catalyst or with the addition of a catalytic amount of 4-(dimethylamino)pyridine, the compound of formula (VIIa) obtained in step (4) is reacted with N,N-carbonyldiimidazole, then hexamethyldisilazane is added, and the mixture is heated at 60-70°C for 15-24 hours, and then a tetrahydrofuran / water binary solvent system is added to obtain compound of formula (Ia).

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