A process for the preparation of evocet and intermediates thereof

Abstract

The present application relates to a kind of preparation method of evocacet and its intermediate, it is the improvement of evocacet synthesis process, using cheap and readily available copper / amino acid catalyst combination, evocacet intermediate is obtained with high yield and high selectivity, compared with prior art reduces production cost.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology and relates to a method for preparing evokalose and its intermediates. Background Technology

[0002] Evocalcet is a calcium receptor agonist (calcimimetic agent) used in Japan to treat secondary hyperparathyroidism (SHPT) in patients on maintenance dialysis, as well as hypercalcemia in patients with parathyroid cancer, those who are ineligible for parathyroidectomy, or those with recurrent primary hyperparathyroidism after parathyroidectomy. It was launched in Japan in May 2018 for the treatment of SHPT in patients on maintenance dialysis. In December 2019, it received partial approval in Japan for the treatment of hypercalcemia in patients with parathyroid cancer or primary hyperparathyroidism who are ineligible for parathyroidectomy or have recurrent parathyroid cancer after parathyroidectomy.

[0003] Evocascene, chemically named 4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidine-1-yl)phenylacetic acid, has the following molecular formula:

[0004]

[0005] Methods for preparing evokine have been reported. Among them, 4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidine-1-yl)phenylacetate (compound 1) is an important intermediate, with the following structure:

[0006]

[0007] Wherein, R is CN or COOR1; R1 is a C1-6 alkyl group, further selected from methyl, ethyl, n-propyl, isopropyl or n-butyl.

[0008] CN105517992B and CN108484469A use cesium carbonate catalyst, palladium acetate, and ethyl 4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidine-1-yl)phenylacetate as a synthetic intermediate for 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos). However, the introduction of palladium acetate greatly increases the likelihood of exceeding the palladium content limit in the product. The standard limit for palladium content is 10 ppm, which is extremely low. Post-treatment to remove palladium through physical and chemical adsorption makes the post-treatment process quite complex. In addition, palladium acetate and its ligand X-PHOS are expensive, resulting in high industrial production costs. Products prepared using the palladium acetate process are off-white to light yellowish-white or grayish-white in appearance, and the product quality is poor.

[0009] CN113620855B provides a method for synthesizing an evokalex intermediate, but the synthesis steps are cumbersome, and other literature has verified that it is impossible to obtain the evokalex active pharmaceutical ingredient with the correct configuration.

[0010] CN116693440A provides a palladium removal method in the evokarse synthesis process. The palladium removal process is cumbersome and not conducive to process scale-up.

[0011] CN117417285A provides a method for synthesizing evokara without the participation of transition metal catalysts, but the synthesis steps are relatively complicated. The reaction process uses active reagents such as acetyl chloride and sodium borohydride, the reaction is significantly exothermic, and the post-processing is difficult, which is not conducive to industrial scale-up.

[0012] CN118405996A provides a method for synthesizing evokalse, but the synthesis steps are relatively complicated and the reaction involves high-risk reactions such as diazotization, which is not conducive to industrial scale-up. Summary of the Invention

[0013] The purpose of this invention is to provide a new method for preparing evokalose and its intermediates, avoiding the use of palladium acetate in the prior art, reducing costs, and improving product quality.

[0014] To achieve the above objectives, the present invention provides the following technical solution:

[0015] In a first aspect, the present invention provides a method for preparing compound 1: compound 1 is prepared by reacting compound 2 or its salt with compound 3 in a solvent in the presence of a base, wherein a ligand and a catalyst are used in the reaction process.

[0016]

[0017] Wherein, R is CN or COOR1; R1 is a C1-6 alkyl group, further selected from methyl, ethyl, n-propyl, isopropyl, or n-butyl;

[0018] The salt of compound 2 is selected from hydrochloride, phosphate, sulfate, oxalate, methanesulfonate or hydrobromide;

[0019] The base is an inorganic base;

[0020] The catalyst is at least one monovalent copper compound;

[0021] The ligand is selected from at least one of N,N-dimethylglycine, N-methylglycine, L-proline, D-proline, and trans-4-hydroxy-L-proline.

[0022] In one embodiment, the ligand in the above reaction is selected from at least one of N,N-dimethylglycine, L-proline, and D-proline.

[0023] In one embodiment, the catalyst in the above reaction is selected from at least one of cuprous iodide, cuprous bromide, cuprous chloride, cuprous oxide, cuprous acetate, cuprous acetylacetone, and cuprous trifluoromethanesulfonate.

[0024] In one embodiment, the catalyst in the above reaction is selected from at least one of cuprous iodide, cuprous bromide, cuprous chloride, and cuprous oxide.

[0025] In one embodiment, the base in the above reaction is selected from at least one of K2CO3, K3PO4, Na2CO3, K2HPO4, NaOH, and KOH.

[0026] In one embodiment, the base used in the above reaction is selected from at least one of K2CO3, K3PO4, and KOH.

[0027] In one embodiment, the solvent in the above reaction is selected from at least one of dimethyl sulfoxide, dimethylformamide, acetonitrile, N,N-dimethylacetamide, N-methylpyrrolidone, and isopropanol.

[0028] In one embodiment, the solvent used in the above reaction is selected from at least one of acetonitrile and N,N-dimethylacetamide.

[0029] In one embodiment, the solvent in the above reaction is acetonitrile.

[0030] In one embodiment, the solvent in the above reaction is a mixed solvent of acetonitrile and dimethyl sulfoxide, with a volume ratio of acetonitrile:dimethyl sulfoxide = 5:0~1.

[0031] In one embodiment, the molar ratio of the ligand to compound 2 in the above reaction is 0.2-0.6:1; further, the molar ratio of the ligand to compound 2 is 0.4:1.

[0032] In one embodiment, the molar ratio of the ligand to copper in the catalyst in the above reaction is 2 to 6:1; further, the molar ratio of the ligand to copper in the catalyst is 4:1.

[0033] In one embodiment, the molar ratio of compound 2 hydrochloride to copper in the copper catalyst in the above reaction is 1:0.06 to 0.1.

[0034] In one embodiment, the molar volume ratio of compound 2 to the solvent in the above reaction is 1:3 to 5 (mol:L).

[0035] In one embodiment, the molar ratio of compound 2 to the base in the above reaction is 1:2 to 4.

[0036] In one embodiment, the reaction temperature in the above reaction is 80-110°C.

[0037] In one embodiment, in the preparation method of compound 1 provided by the present invention, compound 2 has the following structure:

[0038]

[0039] In one embodiment, in the preparation method of compound 1 provided by the present invention, the structures of compound 3 and compound 1 are as follows:

[0040]

[0041] In one embodiment, in the preparation method of compound 1 provided by the present invention, the structures of compound 2, compound 3, and compound 1 are as follows:

[0042]

[0043] Secondly, the present invention also provides a method for preparing evokine, the method comprising the following steps:

[0044] 1) Compound 1 is prepared by the method described in the first aspect of the present invention;

[0045] 2) Prepare evokalse from compound 1 described in step 1).

[0046] In one embodiment, in reaction step 2), compound 1 prepared in step 1) is dissolved in a solvent, a base is added to react, an acid is added to adjust the pH, and the mixture is filtered to obtain crude evokalse.

[0047] In one embodiment, in reaction step 2) above, the solvent is selected from at least one of ethanol, methanol, tetrahydrofuran and water.

[0048] In one embodiment, in reaction step 2) above, the base is selected from at least one of sodium hydroxide, lithium hydroxide, and potassium hydroxide.

[0049] In one embodiment, in reaction step 2) above, the acid is selected from at least one of citric acid, oxalic acid, and hydrochloric acid.

[0050] In one embodiment, in reaction step 2) above, the pH is 7-8.

[0051] In some embodiments, reaction step 2) above also includes a recrystallization step.

[0052] In some embodiments, the crystallization solvent is selected from at least one of dimethyl sulfoxide mixed with ethanol, methanol, acetonitrile, or tetrahydrofuran.

[0053] In some embodiments, the crystallization temperature is 0-10°C.

[0054] The preparation method described in this invention is an improvement on the evokcarthate synthesis process. It utilizes a readily available and inexpensive copper / amino acid catalyst combination, undergoing a coupling reaction under alkaline conditions to obtain the evokcarthate intermediate in high yield and with high selectivity. Compared to the existing palladium acetate / phosphine ligand catalytic system, this method reduces production costs. Furthermore, it eliminates the need for excessive palladium content, avoiding the subsequent cumbersome palladium removal process. In addition, the evokcarthate product prepared from intermediate compound 1 using this process is a white solid with good quality. Detailed Implementation

[0055] The present invention will be further described below with reference to embodiments, enabling those skilled in the art to better understand the invention. These embodiments are merely illustrative and are in no way intended to limit the scope of the invention.

[0056] The meanings of the abbreviations in the conventional synthesis methods, preparation examples, and intermediate synthesis examples are shown in the table below.

[0057] K2CO3: Potassium carbonate

[0058] KHCO3: Potassium bicarbonate

[0059] NaHCO3: Sodium bicarbonate

[0060] Na2CO3: Sodium carbonate

[0061] K3PO4: Potassium phosphate

[0062] Et3N: Triethylamine

[0063] DBU: 1,8-diazaheterocyclic[5,4,0]undec-7-ene

[0064] Na2HPO4: Disodium hydrogen phosphate

[0065] K2HPO4: dipotassium hydrogen phosphate

[0066] NaOH: Sodium hydroxide

[0067] KOH: Potassium hydroxide

[0068] Example 1: Preparation of Compound 1

[0069]

[0070] Compound 2 hydrochloride (313.3 mg, 1.0 mmol), compound 3 (291.7 mg, 1.2 mmol), cuprous iodide (19.1 mg, 0.1 mmol), L-proline (46.1 mg, 0.4 mmol), and dimethyl sulfoxide (5 mL) were added to different reaction flasks; then, 3.0 mmol of different types of base were added to each. The mixtures were heated to 110 °C to prepare compound 1. After the reaction was complete, samples were taken to monitor the reaction solution, and related substances were monitored by HPLC (area normalization method). Specific detection results are shown in the table below:

[0071]

[0072] Note: " / " indicates "not detected". The table only lists the percentage of key related substances. The above explanation applies to all tables in this specification.

[0073] Experimental results show that the reaction conversion rate is high when using K2CO3, K3PO4, Na2CO3, K2HPO4, NaOH, and KOH. Among them, K2CO3, K3PO4, and KOH have the best reaction effect, and the liquid phase ratio of product compound 1 can reach the highest of 31.35%. Organic bases such as Et3N and DBU hardly react under certain conditions.

[0074] Example 2 Preparation of Compound 1

[0075]

[0076] Compound 2 hydrochloride (313.3 mg, 1.0 mmol), compound 3 (291.7 mg, 1.2 mmol), cuprous iodide (19.1 mg, 0.1 mmol), L-proline (46.1 mg, 0.4 mmol), and K₂CO₃ (414.6 mg, 3.0 mmol) were added to different reaction flasks; then 5 mL of different organic solvents were added to each flask, and the mixtures were heated to 110 °C to prepare compound 1. Samples were taken after the reaction to monitor the reaction solution. Related substances were monitored by HPLC (area normalization method). Specific detection results are shown in the table below:

[0077]

[0078] Note: The ethylene glycol condition "18.56 min, 12.84%" and the toluene condition "26.28 min, 32.48%" are indicated separately, meaning that the corresponding impurities were almost undetectable under the experimental conditions described at 17.54 min and 22.24 min, but another impurity with a larger proportion was present at similar retention times of 18.56 min and 26.28 min.

[0079] Experimental results show that dimethylformamide, acetonitrile, N,N-dimethylacetamide, N-methylpyrrolidone, and isopropanol can be used as solvents for effective conversion. Among them, when acetonitrile is used, the liquid phase ratio of product compound 1 is as high as 67.52%.

[0080] Example 3 Preparation of Compound 1

[0081]

[0082] Compound 2 hydrochloride (313.3 mg, 1.0 mmol), compound 3 (291.7 mg, 1.2 mmol), cuprous oxide (7.2 mg, 0.05 mmol), L-proline (46.1 mg, 0.4 mmol), and K₂CO₃ (414.6 mg, 3.0 mmol) were added to different reaction flasks. Acetonitrile (5 mL) and a mixed solvent of acetonitrile and dimethyl sulfoxide (5 / 1, volume ratio, 1) (5 mL) were then added respectively. The mixture was heated to 90 °C to prepare compound 1. Samples of the reaction solution were taken after the reaction was complete to monitor the reaction. Related substances were monitored by HPLC (area normalization method). Specific detection results are shown in the table below:

[0083]

[0084] The reaction results showed that the reaction rate and conversion rate increased when using a mixed solvent of acetonitrile and dimethyl sulfoxide. Therefore, the use of a mixed solvent has a certain promoting effect on the reaction rate and conversion rate.

[0085] Example 4 Preparation of Compound 1

[0086]

[0087] Compound 2 hydrochloride (313.3 mg, 1.0 mmol), compound 3 (388.9 mg, 1.6 mmol), cuprous oxide (7.2 mg, 0.05 mmol), K₂CO₃ (414.6 mg, 3.0 mmol), and acetonitrile (5 mL) were added to different reaction flasks. 0.4 mmol of different ligands were added to each flask, and the mixture was heated to reflux with stirring to prepare compound 1. After the reaction was complete, samples were taken to monitor the reaction solution, and related substances were monitored by HPLC (area normalization method). Specific detection results are shown in the table below:

[0088]

[0089]

[0090] The results showed that effective reactions could occur when N,N-dimethylglycine, N-methylglycine, L-proline, or trans-4-hydroxy-L-proline amino acids were used as ligands; among them, N,N-dimethylglycine and L-proline had better reaction conversion rates and a higher proportion of product compound 1 in the liquid phase.

[0091] Example 5 Preparation of Compound 1

[0092]

[0093] Compound 2 hydrochloride (313.3 mg, 1.0 mmol), compound 3 (388.9 mg, 1.2 mmol), cuprous oxide (7.2 mg, 0.05 mmol), K₂CO₃ (414.6 mg, 3.0 mmol), and acetonitrile (5 mL) were added to different reaction flasks. 0.4 mmol of D-proline and L-proline were added respectively, and the mixture was heated to reflux with stirring to prepare compound 1. After the reaction was complete, samples were taken to monitor the reaction solution, and related substances were monitored by HPLC (area normalization method). Specific detection results are shown in the table below:

[0094]

[0095] The results showed that using D-proline as a ligand was as effective as using L-proline, and both could produce effective reactions with high conversion rates.

[0096] Example 6 Preparation of Compound 1

[0097]

[0098] Compound 2 hydrochloride (313.3 mg, 1.0 mmol), compound 3 (291.7 mg, 1.2 mmol), L-proline (46.1 mg, 0.4 mmol), K2CO3 (414.6 mg, 3.0 mmol), and acetonitrile (5 mL) were added to different reaction flasks, along with different types of copper catalysts. The mixtures were heated to reflux and stirred to prepare compound 1. Samples of the reaction solution were taken after the reaction to monitor related substances. HPLC was used to monitor related substances (area normalization method). Specific detection results are shown in the table below:

[0099]

[0100] Experimental results show that monovalent copper catalysts are more conducive to the reaction than divalent copper catalysts. For example, cuprous iodide, cuprous bromide, cuprous chloride, and cuprous oxide are more conducive to the reaction, and the proportion of product compound 1 in the liquid phase is relatively equal.

[0101] Example 7 Preparation of Compound 1

[0102]

[0103] Compound 2 hydrochloride (313.3 mg, 1.0 mmol), compound 3 (291.7 mg, 1.2 mmol), cuprous iodide (19.1 mg, 0.1 mmol), K₂CO₃ (414.6 mg, 3.0 mmol), and acetonitrile (5 mL) were added to different reaction flasks; then, L-proline in different molar ratios equivalent to compound 2 hydrochloride was added, and the mixture was heated to reflux with stirring to prepare compound 1. After the reaction was completed, samples of the reaction solution were taken for monitoring, and related substances were monitored by HPLC (area normalization method). Specific detection results are shown in the table below:

[0104]

[0105] Experimental results showed that effective reactions could occur with different amounts of ligand, with higher conversion rates observed when the molar ratio of ligand to compound 2 was 0.2-0.6:1. The content of product compound 1 tended to decrease when the molar amount of L-proline ligand was too high or too low. Furthermore, higher conversion rates were observed when the molar ratio of ligand to copper catalyst was 2-6:1.

[0106] Example 8 Preparation of Compound 1

[0107]

[0108] Compound 2 hydrochloride (313.3 mg, 1.0 mmol), compound 3 (388.9 mg, 1.6 mmol), K2CO3 (414.6 mg, 3.0 mmol), and acetonitrile (5 mL) were added to different reaction flasks. Different amounts of cuprous oxide and L-proline were then added, and the mixture was heated to reflux with stirring to prepare compound 1. After 20 hours of reaction, samples were taken to monitor the reaction solution, and related substances were monitored by HPLC (area normalization method). Specific results are shown in the table below:

[0109]

[0110]

[0111] Experimental results show that when the molar ratio of ligand to copper in the copper catalyst is 4:1, the reaction conversion rate increases with the increase of copper catalyst dosage; when the molar ratio of compound 2 hydrochloride to copper in the copper catalyst is 1:0.06 to 0.1, the conversion rate is relatively high.

[0112] Example 9 Preparation of Compound 1

[0113]

[0114] Compound 2 hydrochloride (313.3 mg, 1.0 mmol), compound 3 (388.9 mg, 1.6 mmol), cuprous chloride (7.2 mg, 0.05 mmol), and L-proline (46.1 mg, 0.4 mmol) were added to different reaction flasks, followed by different amounts of K2CO3 and solvent. The mixture was heated to reflux and stirred to prepare compound 1. After 20 hours of reaction, samples were taken to monitor the reaction solution, and related substances were monitored by HPLC (area normalization method). The specific results are shown in the table below:

[0115]

[0116] Experimental results show that the reaction can occur under different amounts of alkali and solvent. The conversion rate is higher when the molar volume ratio (mol:L) of compound 2 hydrochloride to solvent is 1:3–5, but excessive solvent usage tends to decrease the yield of compound 1, while insufficient solvent usage hinders reaction stirring. Effective reactions can occur when the molar ratio of compound 2 hydrochloride to alkali is 1:2–4. Insufficient alkali usage tends to decrease the content of compound 1, while excessive alkali usage hinders reaction stirring. Therefore, increasing the amount of alkali and decreasing the amount of solvent can promote the conversion of compound 2 and increase the yield of product compound 1.

[0117] Example 10 Preparation of Compound 1

[0118]

[0119] To a 250 mL three-necked flask, compound 2 hydrochloride (6.27 g, 20.0 mmol), compound 3 (7.78 g, 32.0 mmol), cuprous oxide (143 mg, 1 mmol), L-proline (0.92 g, 8 mmol), and K₂CO₃ (9.67 g, 70 mmol) were added. Under a nitrogen atmosphere, 60 mL of acetonitrile was added to the reaction flask, and the mixture was heated to reflux with stirring for 20 hours. After the reaction was complete, 120 mL of ethyl acetate and 60 mL of 10% ammonia solution were added to the reaction solution. The mixture was stirred at room temperature for 5 minutes, separated, and the organic phase was collected. The organic phase was then washed once with 60 mL of 10% ammonia solution and once with 60 mL of saturated ammonium chloride solution, and the organic solvent was removed by rotary evaporation to obtain the product, which can be directly used in the next reaction.

[0120] Example 11 Preparation of evacalcet

[0121]

[0122] 20 mL of ethanol and 20 mL of water were added to compound 1 obtained in Example 10, followed by 2 g of sodium hydroxide. The mixture was reacted at 60 °C for 2 hours. After the reaction was complete, the mixture was filtered while hot, and the filtrate was stirred continuously. 3.2 g of citric acid was dissolved in 8 mL of water and slowly added dropwise to the reaction solution. After the solid precipitated, the mixture was kept warm and stirred for 30 min. The citric acid solution was then added dropwise until the pH reached 7-8. After the addition was complete, the mixture was kept warm and stirred for 1 hour, then slowly lowered to 0-10 °C. The mixture was filtered while still warm, and the filter cake was washed with ethanol, dried, and weighed to obtain 3.7 g of evokara, with a purity of 98.98%.

[0123] The crude product was dissolved in dimethyl sulfoxide under a nitrogen atmosphere with stirring. The solution was heated until it dissolved completely. 12 mL of ethanol was added to the system, and the temperature was slowly lowered to 0-10 °C. Crystals were precipitated at this temperature. The solution was filtered, the filter cake was washed with ethanol, dried, and weighed to obtain 3.3 g of evokalse, a white solid with a purity of 99.76%.

Claims

1. A method for preparing compound 1, characterized in that: Compound 1 is prepared by reacting compound 2 or its salt with compound 3 in a solvent in the presence of a base, using ligands and a catalyst in the reaction: Wherein, R is CN or COOR1; R1 is a C1-6 alkyl group; The salt of compound 2 is selected from hydrochloride, phosphate, sulfate, oxalate, methanesulfonate or hydrobromide; The base is an inorganic base; The catalyst is at least one monovalent copper compound; The ligand is selected from at least one of N,N-dimethylglycine, N-methylglycine, L-proline, D-proline, and trans-4-hydroxy-L-proline.

2. The preparation method according to claim 1, wherein the catalyst is selected from at least one of cuprous iodide, cuprous bromide, cuprous chloride, cuprous oxide, cuprous acetate, cuprous acetylacetone, and cuprous trifluoromethanesulfonate; preferably at least one of cuprous iodide, cuprous bromide, cuprous chloride, and cuprous oxide.

3. The preparation method according to claim 1 or 2, wherein the ligand is selected from at least one of N,N-dimethylglycine, L-proline, and D-proline.

4. The preparation method according to any one of claims 1 to 3, wherein the alkali is selected from at least one of K2CO3, K3PO4, Na2CO3, K2HPO4, NaOH, and KOH.

5. The preparation method according to any one of claims 1 to 4, wherein the solvent is selected from at least one of dimethyl sulfoxide, dimethylformamide, acetonitrile, N,N-dimethylacetamide, N-methylpyrrolidone, and isopropanol.

6. The preparation method according to any one of claims 1 to 5, wherein the molar ratio of the ligand to compound 2 is 0.2 to 0.6:

1.

7. The preparation method according to any one of claims 1 to 6, wherein the molar ratio of the ligand to copper in the catalyst is 2 to 6:

1.

8. The preparation method according to any one of claims 1 to 7, wherein the molar volume ratio of compound 2 to the solvent is 1:3 to 5.

9. The preparation method according to any one of claims 1 to 8, wherein the molar ratio of compound 2 to the base is 1:2 to 4.

10. A method for preparing evokort, characterized in that, The method includes the following steps: 1) Compound 1 is prepared by the method according to any one of claims 1 to 9; 2) Prepare evokalse from compound 1 described in step 1).

Images