A method for synthesizing cinalikacide hydrochloride

Abstract

The application discloses a synthesis method of cinacalcet hydrochloride, and comprises the following steps: mixing 3-trifluoromethyl phenylpropanol, (R)-1-(1-naphthyl)ethylamine, a catalyst and diphenyl phosphate, stirring under the protection of nitrogen or inert gas at 120-130 DEG C for 15-25 hours, cooling to room temperature, adding n-hexane to obtain a mixed solution, pouring the mixed solution into hydrochloric acid, standing until white solids are precipitated, filtering and drying to obtain the cinacalcet hydrochloride, wherein the catalyst is 1-hydroxytetraphenylcyclopentadienyl(tetraphenyl-2,4-cyclopentadienyl-1-ketone)-mu-hydroxytetracarbonyl diruthenium (II), the synthesis method is simple in steps, the cinacalcet hydrochloride is synthesized in one step, the catalyst used is cheap, the yield is high, the cost is obviously reduced, and the method is suitable for large-scale production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of cinacalcet hydrochloride. BACKGROUND

[0002] Cinacalcet hydrochloride is a calcium sensing receptor agonist, and its chemical name is N-((1R)-1-(1-naphthyl)ethyl)-3-(3-(trifluoromethyl)phenyl)propan-1-amine hydrochloride. It is developed by NPS Pharmaceuticals Company in the United States, and is clinically used for treating secondary hyperparathyroidism (SHPT) caused by chronic kidney disease and receiving dialysis, and hypercalcemia in patients with parathyroid tumors.

[0003] At present, the main process routes for synthesizing cinacalcet hydrochloride disclosed in the prior art are as follows:

[0004] Process route one:

[0005]

[0006] In process route one, the alcohol hydroxyl group of 3-trifluoromethyl phenylpropanol is converted into Cl - or OMs leaving group, and is reacted with (R)-1-(1-naphthyl)ethylamine, and the leaving group is finally removed in the form of reaction waste, which means that the reaction has poor atom economy, and the process route has problems such as that the reaction waste is not easy to handle and a large amount of organic solvent is used in the reaction process, so that the industrial production cost is high.

[0007] Process route two:

[0008]

[0009] In process route two, the alcohol hydroxyl group of 3-trifluoromethyl phenylpropanol is oxidized into an aldehyde group by an oxidizing agent, and is reacted with (R)-1-(1-naphthyl)ethylamine, and process route two needs to use a large amount of oxidizing agent, reducing agent, condensing agent and organic solvent, which will generate a large amount of waste, so that the atom economy is poor. In addition, the aldehyde group has a very high requirement for anhydrous in the condensation reaction with imine, which brings great trouble to the whole reaction, and sodium cyanoborohydride is used in the reduction reaction, which is a toxic product, and the post-treatment is more troublesome, and toxic gas is released, which is not conducive to large-scale production. Therefore, the existing synthesis method of cinacalcet hydrochloride has many problems. SUMMARY

[0010] In view of the deficiencies of the prior art, the purpose of the present application is to provide a synthesis method of cinacalcet hydrochloride.

[0011] The purpose of the present application is achieved by the following technical scheme.

[0012] A method for synthesizing cinacalcet hydrochloride includes the following steps:

[0013] 3-Trifluoromethylphenylpropanol, (R)-1-(1-naphthyl)ethylamine, catalyst, and diphenyl phosphate were mixed and stirred at 120–130 °C for 15–25 hours under nitrogen or inert gas protection. After the reaction was completed, the mixture was cooled to room temperature, and n-hexane was added to obtain a mixed solution. The mixed solution was poured into hydrochloric acid and allowed to stand until a white solid precipitated. The solid was filtered and dried to obtain cinacalcet hydrochloride. The catalyst was 1-hydroxytetraphenylcyclopentadienyl(tetraphenyl-2,4-cyclopentadienyl-1-one)-μ-hydroxytetracarbonyl ruthenium(II) (Shvo's catalyst). The ratio of 3-trifluoromethylphenylpropanol, (R)-1-(1-naphthyl)ethylamine, catalyst, and diphenyl phosphate was 1:(1–1.05):(0.0005–0.0015):0.2 by molar amount.

[0014] In the above technical solution, the mass fraction of 3-trifluoromethylphenylpropanol, the volume fraction of n-hexane, and the volume fraction of hydrochloric acid are in the ratio of 2.04:(8-15):(2-4), where the mass fraction is in g and the volume fraction is in mL.

[0015] In the above technical solution, the concentration of HCl in the hydrochloric acid is 2-4 mol / L.

[0016] In the above technical solution, the settling time is 15 to 24 hours.

[0017] In the above technical solution, the drying temperature is 20-25℃ and the drying time is 1-2 hours.

[0018] Compared with the prior art, the present invention has the following beneficial effects:

[0019] The synthesis method of this invention is simple and can synthesize cinacalcet hydrochloride in one step. It does not require the use of large amounts of oxidants, reducing agents and organic solvents. No solvent is required to participate in the reaction. The 1-hydroxytetraphenylcyclopentadienyl(tetraphenyl-2,4-cyclopentadienyl-1-one)-μ-hydroxytetracarbonyl ruthenium(II) used is inexpensive. It significantly reduces costs while achieving high yield and is suitable for large-scale production. Attached Figure Description

[0020] Figure 1 The 1H NMR spectrum of cinacalcet hydrochloride prepared in Example 1. Detailed Implementation

[0021] The technical solution of the present invention will be further described in detail below with reference to the accompanying drawings and embodiments.

[0022] 1-Hydroxytetraphenylcyclopentadienyl(tetraphenyl-2,4-cyclopentadienyl-1-one)-μ-hydroxytetracarbonyl ruthenium(II) was purchased from Anaiji Chemical, CAS No.: 104439-77-2, official website price: 398 yuan / gram (g);

[0023] Dichloro(pentamethylcyclopentadiene)iridium(III) dimer was purchased from Anaiji Chemical, CAS No.: 12354-84-6, with an official website price of 1620 yuan / gram (g).

[0024] In the following examples, 1-hydroxytetraphenylcyclopentadienyl(tetraphenyl-2,4-cyclopentadienyl-1-one)-μ-hydroxytetracarbonyl diruthenium(II), dodecyltriruthenium, ruthenium trichloride, tris(triphenylphosphine)ruthenium dichloride(II), dichloro(pentamethylcyclopentadiene)iridium(III) dimer, 1,5-cyclooctadiene iridium chloride dimer, methoxy(cyclooctadiene)iridium(I) dimer, dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer, and di(1,5-cyclooctadiene)tetrafluoroborate (I) were used as catalysts.

[0025] Example 1

[0026] A method for synthesizing cinacalcet hydrochloride includes the following steps:

[0027]

[0028] 3-Trifluoromethylphenylpropanol (2.04 g, 10 mmol), (R)-1-(1-naphthyl)ethylamine (1.71 g, 10 mmol), catalyst (10 mg, 0.01 mmol), and diphenyl phosphate (0.5 g, 2 mmol) were mixed and stirred at 125 °C for 24 hours under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature of 20–25 °C, and 10 mL of n-hexane was added to obtain a mixed solution. The mixed solution was poured into 4 mL of hydrochloric acid (HCl concentration of 2 mol / L), and allowed to stand for 24 hours. A white solid precipitated, which was filtered and dried at room temperature of 20–25 °C for 1 hour to obtain cinacalcet hydrochloride. Yield: 3.3 g, yield: 85%. The catalyst was 1-hydroxytetraphenylcyclopentadienyl(tetraphenyl-2,4-cyclopentadienyl-1-one)-μ-hydroxytetracarbonyl ruthenium(II) (Shvo's catalyst).

[0029] The 1H NMR spectrum of cinacalcet hydrochloride prepared in Example 1 is as follows: Figure 1 As shown, by Figure 1 It can be seen that cinacalcet hydrochloride was successfully synthesized.

[0030] Example 2

[0031] A method for synthesizing cinacalcet hydrochloride includes the following steps:

[0032] 3-Trifluoromethylphenylpropanol (20.4 g, 100 mmol), (R)-1-(1-naphthyl)ethylamine (17.1 g, 100 mmol), catalyst (100 mg, 0.1 mmol), and diphenyl phosphate (5 g, 20 mmol) were mixed and stirred at 130 °C for 24 hours under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature of 20–25 °C, and 100 mL of n-hexane was added to obtain a mixed solution. The mixed solution was poured into 20 mL of hydrochloric acid (HCl concentration of 2 mol / L), and allowed to stand for 24 hours. A white solid precipitated, which was filtered and dried at room temperature of 20–25 °C for 1 hour to obtain cinacalcet hydrochloride. Yield: 32.8 g, yield: 83%. The catalyst was 1-hydroxytetraphenylcyclopentadienyl(tetraphenyl-2,4-cyclopentadienyl-1-one)-μ-hydroxytetracarbonyl diruthenium(II).

[0033] Example 3

[0034] A method for synthesizing cinacalcet hydrochloride includes the following steps:

[0035] 3-Trifluoromethylphenylpropanol (40.8 g, 200 mmol), (R)-1-(1-naphthyl)ethylamine (34.2 g, 200 mmol), catalyst (200 mg, 0.2 mmol), and diphenyl phosphate (10 g, 40 mmol) were mixed and stirred at 130 °C for 24 hours under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature of 20–25 °C, and 300 mL of n-hexane was added to obtain a mixed solution. The mixed solution was poured into 40 mL of hydrochloric acid (HCl concentration of 2 mol / L), and allowed to stand for 24 hours. A white solid precipitated, which was filtered and dried at room temperature of 20–25 °C for 2 hours to obtain cinacalcet hydrochloride. Yield: 65.2 g, yield: 83%. The catalyst was 1-hydroxytetraphenylcyclopentadienyl(tetraphenyl-2,4-cyclopentadienyl-1-one)-μ-hydroxytetracarbonyl diruthenium(II).

[0036] In Examples 1-3 of this invention, 1-hydroxytetraphenylcyclopentadienyl(tetraphenyl-2,4-cyclopentadienyl-1-one)-μ-hydroxytetracarbonyl ruthenium(II) was used as a catalyst. This catalyst is priced at 398 RMB / gram on the website of Anaiji Chemical, making it inexpensive, suitable for practical applications, and scale-up experiments do not affect its yield. The reaction yield is high while the cost is significantly reduced.

[0037] Comparative Example 1

[0038] A method for synthesizing cinacalcet hydrochloride is basically the same as the method in Example 3, except that the catalyst is different. The catalyst used in the synthesis method of Comparative Example 1 is an iridium catalyst. The iridium catalyst is [Ir] prepared in the literature Scalable Synthesis of Antihistamines and Sensipar via Intensified Hydrogen Borrowing Methodology, ACS Sustainable Chem. Eng. 2023, 11, 12389. In this literature, the iridium catalyst is synthesized from dichloro(pentamethylcyclopentadiene)iridium(III) dimer as a raw material.

[0039] The synthetic method of Comparative Example 1 yielded 80% cinacalcet hydrochloride.

[0040] The iridium catalyst used in the synthesis method of Comparative Example 1 is not commercially available and needs to be prepared from commercially available dichloro(pentamethylcyclopentadiene)iridium(III) dimer. However, dichloro(pentamethylcyclopentadiene)iridium(III) dimer is expensive (1620 yuan / gram), which is not conducive to practical production. Moreover, the yield of the synthesized iridium catalyst is only 85%, which not only results in a large waste of raw materials but also consumes a lot of time, manpower, and material resources in the production process, further reducing its feasibility and economic benefits in practical applications. Considering the raw material, labor, and time costs of preparing this iridium catalyst, the synthesis price of [Ir] is expected to exceed 4000 yuan / gram.

[0041] Comparative Examples 2-9

[0042] A method for synthesizing cinacalcet hydrochloride is basically the same as the method in Example 1, except for the catalyst. The catalysts used in the synthesis methods of Comparative Examples 2 to 9 are shown in Table 1.

[0043] Table 1

[0044] Comparative Example Catalyst Yield of cinacalcet hydrochloride Comparative Example 2 Triruthenium dodecacarbonyl 9％ Comparative Example 3 Ruthenium trichloride 4％ Comparative Example 4 Tris(triphenylphosphine) ruthenium (II) dichloride 4％ Comparative Example 5 Dichloro(pentamethylcyclopentadienyl) iridium (III) dimer 2％ Comparative Example 6 1,5-Cyclooctadiene iridium chloride dimer 3％ Comparative Example 7 Methoxy(cyclooctadiene) iridium (I) dimer 4％ Comparative Example 8 Dichloro(pentamethylcyclopentadienyl) rhodium (III) dimer 8％ Comparative Example 9 Bis(1,5-cyclooctadiene) rhodium (I) tetrafluoroborate 4％

[0045] The present invention has been described above by way of example. It should be noted that any simple modifications, alterations or other equivalent substitutions that can be made by those skilled in the art without creative effort without departing from the core of the present invention fall within the protection scope of the present invention.

Claims

1. A method for synthesizing cinacalcet hydrochloride, characterized in that, Includes the following steps: 3-Trifluoromethylphenylpropanol, (R)-1-(1-naphthyl)ethylamine, catalyst, and diphenyl phosphate were mixed and stirred at 120–130 °C for 15–25 hours under nitrogen or inert gas protection. After the reaction was completed, the mixture was cooled to room temperature, and n-hexane was added to obtain a mixed solution. The mixed solution was poured into hydrochloric acid and allowed to stand until a white solid precipitated. The solid was filtered and dried to obtain cinacalcet hydrochloride. The catalyst was 1-hydroxytetraphenylcyclopentadienyl(tetraphenyl-2,4-cyclopentadienyl-1-one)-μ-hydroxytetracarbonyl ruthenium(II). The molar ratio of 3-trifluoromethylphenylpropanol, (R)-1-(1-naphthyl)ethylamine, catalyst, and diphenyl phosphate was 1:(1–1.05):(0.0005–0.0015):0.

2.

2. The synthesis method according to claim 1, characterized in that, The mass fraction of 3-trifluoromethylphenylpropanol, the volume fraction of n-hexane, and the volume fraction of hydrochloric acid are in the ratio of 2.04:(8-15):(2-4), where the mass fraction is in g and the volume fraction is in mL.

3. The synthesis method according to claim 1, characterized in that, The concentration of HCl in hydrochloric acid is 2–4 mol / L.

4. The synthesis method according to claim 1, characterized in that, The settling time is 15 to 24 hours.

5. The synthesis method according to claim 1, characterized in that, The drying temperature is 20-25℃, and the drying time is 1-2 hours.

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