Preparation method of cinacalcet hydrochloride and intermediate thereof

Abstract

The invention discloses a preparation method of cinacalcet hydrochloride and an intermediate thereof. The invention provides a cinacalcet II preparation method, which comprises: in a solvent, carrying out a reduction reaction on 3-(3-trifluoromethyl-phenyl)-N-(R)-(1-naphthyl-1-ethyl)-propanamide and a reducing agent, and after the reaction is completed, carrying out a quenching reaction by using a metal sulfate hydrate to obtain cinacalcet II, the reducing agent is an alkali metal hydroboron and boron trifluoride system; the structural general formula of the hydrated sulfuric acid metal salt is Mx (SO4) y.zH2O, M is one or more of metal ions and ammonium radicals of a first period, a second period, a third period and a fourth period in a periodic table of elements, x is 1-2, y is 1-3, and z is 0-20. The preparation method is simple, high in safety, low in equipment requirement and suitable for industrial production, and the prepared cinacalcet hydrochloride product is high in purity and yield. # imgabs0 #

Description

[0001] This application is a divisional application of the invention patent application with the application date of October 29, 2019, application number 201911037742.0, and invention title "Preparation Method of Cinacalcet Hydrochloride and Its Intermediate". Technical Field

[0002] The present invention relates to a preparation method of cinacalcet hydrochloride and its intermediate. Background Art

[0003] Cinacalcet Hydrochloride (I), known as the first drug in a new class of compounds called calcimimetics, can activate calcium receptors in the parathyroid gland, thereby reducing the secretion of parathyroid hormone. This product can regulate the behavior of parathyroid calcium receptors, and by enhancing the sensitivity of the receptor to the calcium level in the bloodstream, reduce the levels of parathyroid hormone, calcium, phosphorus, and calcium-phosphorus complexes. Cinacalcet Hydrochloride was developed by NPS Pharmaceuticals in the United States. On March 8, 2004, the FDA approved the listing of Cinacalcet Hydrochloride produced by Amgen (the licensee of this product of NPS Pharmaceuticals), with the trade name Sensipar; in October 2007, Cinacalcet Hydrochloride produced by Kirin Pharmaceutical Co., Ltd. was listed in Japan, with the trade name REGPARA, and the specifications are 25 mg and 75 mg (calculated as cinacalcet).

[0004]

[0005] Cinacalcet Hydrochloride is used to treat secondary hyperparathyroidism in patients with chronic kidney disease undergoing dialysis, hypercalcemia in patients with parathyroid carcinoma, etc. Patients with chronic renal failure often suffer from abnormal bone metabolism and mineralization, manifested as osteoporosis, osteomalacia, etc., that is, renal osteodystrophy. After end-stage renal disease patients are treated with cinacalcet, the laboratory indicators reflecting bone metabolism can basically return to normal, and the symptoms of renal osteopathy such as movement disorders and bone pain can be significantly improved. These effects are achieved by reducing serum parathyroid hormone. Calciphylaxis is a relatively rare complication in patients with chronic renal failure, and the prognosis is very poor. This disease is mainly manifested as skin and soft tissue ulcers, necrosis, pain, and secondary infections, etc. Serum hypercalcemia and hyperphosphatemia are the most important risk factors for calciphylaxis. All along, there has been a lack of effective treatment methods for this disease, and parathyroidectomy can only relieve the condition to a certain extent. The treatment of calciphylaxis with cinacalcet combined with bisphosphonates and sodium thiosulfate can promote ulcer healing and relieve the pain of patients.

[0006] Currently, the reported preparation methods of cinacalcet hydrochloride mainly include:

[0007] (1) Reductive amination method;

[0008] Patent US6211244 discloses the preparation of cinacalcet hydrochloride by reductive amination. Due to the toxicity of the reducing agent sodium cyanoborohydride, the high price, easy hydrolysis, and difficulty in scale-up operation of titanium tetraisopropoxide, and the inevitable generation of over-reduced impurities in the subsequent process, there are problems such as difficult operation, cumbersome purification, low yield, and unsuitability for industrial production.

[0009]

[0010] (2) Alkylation method

[0011] Literature CN101180261 discloses the direct alkylation method of methanesulfonate.

[0012]

[0013] This method uses 3-(trifluoromethyl)phenylpropanol as the raw material, and synthesizes cinacalcet hydrochloride by reacting with (R)-1-naphthylethylamine through halogenation or esterification reaction. The reaction easily generates disubstituted impurities that are difficult to remove. In addition, both the starting material and the generated intermediate are liquids and are difficult to purify, and the quality of the product is difficult to control, which is not conducive to industrial production.

[0014] (3) Amide reduction method

[0015] Patents such as WO2007127445, WO2008117299, and CN201210577243 disclose the method of reducing 3-(3-trifluoromethyl-phenyl)-N-(R)-(1-naphthalen-1-yl-ethyl)-propanamide (amide intermediate) to prepare cinacalcet hydrochloride. The total yield of this method is 58% - 62%. The amide intermediate is prepared from 3-trifluoromethylbenzoyl chloride and then (R)-1-naphthylethylamine.

[0016]

[0017] Currently, method three is the most widely used, but in the reduction of the amide intermediate in the synthesis route, lithium aluminum hydride or a metal borate and Lewis acid (boron trifluoride tetrahydrofuran, boron trifluoride diethyl ether, aluminum trichloride, sulfuric acid, iodine, etc.) system is mostly used. When these reducing agents are quenched during post-treatment, a large amount of hydrogen and hydrogen fluoride will be generated, the exotherm is intense, it is easy to have material overflow and explosion risk; in some conditions, the generated hydrogen fluoride is also easy to corrode the equipment, which is not suitable for industrial production.

[0018] Therefore, it is an urgent technical problem to be solved at present to find a method for reducing 3-(3-trifluoromethyl-phenyl)-N-(R)-(1-naphthalen-1-yl-ethyl)-propanamide to prepare cinacalcet, with mild post-treatment conditions, simple operation, low equipment requirements, high safety, high yield, and suitability for industrial production. Summary of the Invention

[0019] The technical problem to be solved by the present invention is to overcome the defects in the prior art such as the cumbersome post-treatment operation steps, low yield, high production cost, and high risk in industrial production of the preparation method of cinacalcet hydrochloride, and to provide a preparation method of cinacalcet hydrochloride and its intermediate. The preparation method of the present invention is simple, has high safety, low equipment requirements, and is suitable for industrial production. The obtained cinacalcet hydrochloride product has high purity (purity greater than 99.0%, single impurity less than 0.10%, optical isomer less than 0.15%, meeting the requirements of bulk drugs) and high yield (80% - 83%).

[0020] The present invention provides a preparation method of cinacalcet II, which comprises the following steps: in a solvent, 3-(3-trifluoromethyl-phenyl)-N-(R)-(1-naphthalen-1-yl-ethyl)-propanamide (Compound I) is subjected to a reduction reaction with a reducing agent, and after the reaction is completed, the reaction is quenched with a hydrated metal sulfate to obtain cinacalcet II; the reducing agent is a system of alkali metal borohydride and boron trifluoride; the general structural formula of the hydrated metal sulfate is M x (SO4) y ·zH2O, wherein M is one or more of metal ions in the first, second, third, and fourth periods of the periodic table of elements and ammonium radical, x is 1 - 2, y is 1 - 3, and z is 0 - 20;

[0021]

[0022] In the preparation method of cinacalcet II, the alkali metal borohydride is preferably sodium borohydride and / or potassium borohydride.

[0023] In the preparation method of cinacalcet II, the "metal ions in the first, second, third, and fourth periods of the periodic table of elements" are preferably alkali metal ions, alkaline earth metal ions, and metal ions of Group IIIA in the first, second, third, and fourth periods of the periodic table of elements; the "alkali metal ions in the first, second, third, and fourth periods of the periodic table of elements" are preferably sodium ions, potassium ions, or lithium ions; the "alkaline earth metal ions in the first, second, third, and fourth periods of the periodic table of elements" are preferably magnesium ions; the "metal ions of Group IIIA in the first, second, third, and fourth periods of the periodic table of elements" are preferably aluminum ions.

[0024] In the preparation method of cinacalcet II, the ratio of y to x is preferably 0.5 - 3, such as 0.5, 1.0, 1.5, 2.0, or 3.0.

[0025] In the preparation method of cinacalcet II, z is preferably 5 - 15, such as 7, 10, or 12.

[0026] In the preparation method of cinacalcet II described above, the M x (SO4) y is preferably M2SO4, MSO4, M(SO4)2 or M2(SO4)3. The MSO4 can be MgSO4; the M2SO4 can be K2SO4 and / or Na2SO4; the M(SO4)2 can be KAl(SO4)2, NaAl(SO4)2, NH4Al(SO4)2, (NH4)2Fe(SO4)2 or (NH4)2Cu(SO4)2; the M2(SO4)3 can be Al2(SO4)3, Na2Fe2(SO4)3, Na2Ni2(SO4)3 or Na2Mn2(SO4)3. The M x (SO4) y ·zH2O is further preferably Na2SO4·10H2O, KAl(SO4)2·12H2O or MgSO4·7H2O.

[0027] In the preparation method of cinacalcet II described above, the molar ratio of the hydrated metal sulfate to the compound I is preferably 1 to 20, more preferably 2 to 15, such as 3, 5 or 7.

[0028] In the preparation method of cinacalcet II described above, the solvent is preferably an ether solvent; the ether solvent is preferably tetrahydrofuran.

[0029] In the preparation method of cinacalcet II described above, the volume-mass ratio of the solvent to the compound I is preferably 1 mL / g to 10 mL / g, more preferably 3 mL / g to 8 mL / g, such as 5 mL / g.

[0030] In the preparation method of cinacalcet II described above, in the "alkali metal borohydride and boron trifluoride system", the molar ratio of the alkali metal borohydride to the boron trifluoride is preferably 1.

[0031] In the preparation method of cinacalcet II described above, the molar ratio of the reducing agent to the compound I is preferably 1 to 5, more preferably 1.5 to 3.

[0032] In the preparation method of cinacalcet II described above, the temperature of the reduction reaction is preferably 0 to 100 °C, more preferably 50 °C to 80 °C, such as 60 °C to 70 °C.

[0033] In the method for preparing cinacalcet II, the progress of the reduction reaction can be monitored by conventional monitoring methods in the art (such as TLC, HPLC or NMR). Generally, the reaction end point is when the content of compound I is less than 1%. The time of the reduction reaction is preferably 1 hour to 10 hours, more preferably 3 hours to 8 hours, for example, 5 hours.

[0034] In the method for preparing cinacalcet II, the reduction reaction preferably comprises the following steps: adding an alkali metal borohydride to a mixture formed by compound I and a solvent, then adding boron trifluoride, stirring, heating up to continue the reaction. After the reaction is completed, cooling is carried out to quench the reaction, and then cinacalcet II can be obtained.

[0035] The temperature of the "mixture formed by compound I and a solvent" is preferably 0 to 10 °C. The "adding of the alkali metal borohydride" is preferably carried out in batches, and the adding rate is controlled so that the temperature of the reaction system does not exceed 10 °C. The "adding of boron trifluoride" is preferably carried out by dropwise addition, and the dropping rate is maintained so that the reaction temperature of the system does not exceed 10 °C. The temperature of the "heating up to continue the reaction" is preferably 60 °C to 70 °C. The time of the "heating up to continue the reaction" is preferably 3 hours to 8 hours, for example, 5 hours.

[0036] In the method for preparing cinacalcet II, the temperature of the "quenching reaction" is preferably 5 °C to 40 °C, more preferably 10 °C to 35 °C, for example, 10 °C to 15 °C, 20 °C to 25 °C or 30 °C to 35 °C.

[0037] In the method for preparing cinacalcet II, the time of the "quenching reaction" is preferably 1 hour to 12 hours, more preferably 3 hours to 8 hours, for example, 3 hours to 4 hours, 5 hours to 6 hours or 7 hours to 8 hours.

[0038] The method for preparing cinacalcet II preferably comprises the following post-treatment steps: after quenching the reaction, stirring, filtering, adjusting the pH to 8 - 9, extracting, washing, drying, filtering, and concentrating to obtain cinacalcet II. The filtering, concentrating, stirring, and drying can be carried out by conventional methods for such operations in the art. The solvent used for extraction is preferably an ester solvent, and the ester solvent is preferably ethyl acetate. The pH adjustment is preferably carried out using an inorganic base, and the inorganic base is preferably sodium hydroxide. The sodium hydroxide is preferably used in the form of its aqueous solution, and the concentration of the sodium hydroxide aqueous solution is preferably 2N (i.e., 2 mol / L).

[0039] The concentration is preferably vacuum concentration; the temperature of the vacuum concentration is preferably 45°C to 55°C, and the pressure of the vacuum concentration is preferably -0.08 MPa to -0.1 MPa. The drying is preferably vacuum drying; the temperature of the vacuum drying is preferably 45°C to 55°C; the time of the vacuum drying is preferably 12 hours to 16 hours; the pressure of the vacuum drying is preferably -0.01 MPa to -0.1 MPa.

[0040] The present invention also provides a preparation method of cinacalcet hydrochloride III, which comprises the following steps: after obtaining cinacalcet II according to the above method, then carrying out a salt-forming reaction on the cinacalcet II with hydrochloric acid to obtain cinacalcet hydrochloride III;

[0041]

[0042] The preparation method of the cinacalcet hydrochloride III can adopt the conventional methods of this kind of salt-forming reaction in the art. The following reaction methods and conditions are preferred in the present invention:

[0043] The preparation method of the cinacalcet hydrochloride III can be carried out in a solvent or under solvent-free conditions. When the preparation method of the cinacalcet hydrochloride III is carried out in a solvent, the solvent is preferably a nitrile solvent; the nitrile solvent is preferably acetonitrile. When the preparation method of the cinacalcet hydrochloride III is carried out in a solvent, the volume / mass ratio of the solvent to the cinacalcet II is preferably 1 mL / mg to 10 mL / mg, more preferably 2 mL / mg to 6 mL / mg, such as 3 mL / mg.

[0044] In the preparation method of the cinacalcet hydrochloride III, the hydrochloric acid is preferably concentrated hydrochloric acid. The concentrated hydrochloric acid can be a conventional commercially available concentrated hydrochloric acid reagent, and the molar concentration of the concentrated hydrochloric acid is preferably 12 mol / L.

[0045] In the preparation method of the cinacalcet hydrochloride III, the volume / mass ratio of the hydrochloric acid to the cinacalcet II is preferably 0.1 mL / mg to 10 mL / mg, more preferably 0.15 mL / mg to 0.5 mL / mg, such as 0.24 mL / mg, 0.25 mL / mg or 0.26 mL / mg.

[0046] In the preparation method of the cinacalcet hydrochloride III, the temperature of the salt-forming reaction is preferably 10°C to 40°C, more preferably 20°C to 30°C, such as 25°C or 30°C.

[0047] In the method for preparing cinacalcet hydrochloride III, the progress of the salt formation reaction can be monitored by conventional monitoring methods in the art (such as TLC, HPLC or NMR). Generally, the end point of the reaction is when cinacalcet II disappears. The time of the salt formation reaction is preferably 1 hour to 10 hours, more preferably 1 hour to 5 hours, for example 1 hour to 3 hours.

[0048] The method for preparing cinacalcet hydrochloride III preferably comprises the following steps: adding hydrochloric acid to cinacalcet II for salt formation reaction to obtain cinacalcet hydrochloride III. The addition method is preferably dropwise addition, and the dropping rate is such that the system temperature is maintained not exceeding 40°C.

[0049] The method for preparing cinacalcet hydrochloride III preferably comprises the following post-treatment steps: after the reaction is completed, adding water, stirring, and filtering to obtain cinacalcet hydrochloride III.

[0050] On the basis of not violating the common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain various preferred examples of the present invention.

[0051] The reagents and raw materials used in the present invention are all commercially available.

[0052] In the present invention, the room temperature refers to the ambient temperature, which is 10°C to 35°C.

[0053] The positive and progressive effects of the present invention are as follows: the preparation method of the present invention is simple, has high safety, low equipment requirements, is suitable for industrial production, the prepared cinacalcet hydrochloride product has high purity, the purity is greater than 99.0%, the single impurity is less than 0.10%, the optical isomer is less than 0.15%, meets the requirements of the bulk drug, has high yield (80% - 83%), and is suitable for industrial production.

[0054] The present invention will be further illustrated by the following examples, but the present invention is not limited to the scope of the examples. The experimental methods without specific conditions in the following examples are carried out according to conventional methods and conditions, or selected according to the product instructions. Specific Embodiments

[0055] Example 1

[0056]

[0057] 3-(3-Trifluoromethyl-phenyl)-N-(R)-(1-naphthalen-1-yl-ethyl)-propanamide (Compound I) (9 Kg, 24.2 mol) was added to 45 L of tetrahydrofuran. Stirring was started, and the temperature was lowered to 0 - 10 °C. 1380 g of sodium borohydride (36.3 mol) was added, and 10.17 Kg of a 50% by mass boron trifluoride tetrahydrofuran solution (36.3 mol) (the mass percentage refers to the mass of boron trifluoride in the total mass of the boron trifluoride tetrahydrofuran solution) was added dropwise. After the dropwise addition, the mixture was stirred at 0 - 10 °C for 1 hour, then heated to 60 - 70 °C and reacted for 5 hours. When the content of the raw material (Compound I) monitored by HPLC was less than 1%, the reaction was stopped. It was cooled to 20 - 25 °C, 27 L of ethyl acetate was added to dilute the reaction solution, and 39 Kg of NaSO4·10H2O (sodium sulfate decahydrate, 121 mol) was added in batches slowly at 20 - 25 °C to quench the reaction. After the addition, the temperature was raised to 60 - 65 °C and stirred for 5 - 6 hours, then cooled to room temperature (25 °C), filtered. The organic phase was adjusted to pH = 8 - 9 with 25 L of an aqueous sodium hydroxide solution (2 mol / L), extracted twice with ethyl acetate, the organic phases were combined, washed with water, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum (-0.08 MPa to -0.1 MPa) at 45 °C - 55 °C to obtain 9 Kg of cinacalcet II with a yield of 100%.

[0058] The above 9 Kg of cinacalcet II was added to 27 L of acetonitrile. Stirring was started, and 2.3 L of commercially available concentrated hydrochloric acid (12 mol / L) was added at room temperature (25 °C). The mixture was stirred for 1 - 3 hours, 81 L of water was added thereto, and the mixture was stirred at room temperature for 12 - 15 hours, then filtered. The filter cake was dried under vacuum at 45 °C - 55 °C for 12 - 16 hours to obtain 7.9 Kg of cinacalcet hydrochloride III with an HPLC purity of 99.50%, a maximum single impurity of 0.05%, and a yield of 82.8% (calculated based on Compound I).

[0059] Example 2

[0060] Compound I (600 g, 1.62 mol) was added to 3.0 L of tetrahydrofuran. Stirring was initiated, and the temperature was lowered to 0 - 10 °C. 92 g of sodium borohydride (2.4 mol) was added, and 678 g of a 50% by mass boron trifluoride tetrahydrofuran solution (2.4 mol) (the mass percentage refers to the mass of boron trifluoride in the total mass of the boron trifluoride tetrahydrofuran solution) was added dropwise. After the dropwise addition, the mixture was stirred at 0 - 10 °C for 1 hour, then heated to 60 - 70 °C and kept reacting for 5 hours. When the content of the raw material (Compound I) monitored by HPLC was less than 1%, the reaction was stopped. It was cooled to 10 - 15 °C, 1.8 L of ethyl acetate was added to dilute the reaction solution, and 2.3 Kg of KAl(SO4)2·12H2O (potassium alum, 4.85 mol) was added slowly in batches at 10 - 15 °C to quench the reaction. The quenching process was very gentle. After the addition, the temperature was raised to 50 - 55 °C and stirred for 7 - 8 hours. Then it was cooled to room temperature (30 °C), filtered. The organic phase was adjusted to pH = 8 - 9 with an aqueous sodium hydroxide solution (2 mol / L), extracted twice with ethyl acetate, the organic phases were combined, washed with water, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum (-0.08 MPa - -0.1 MPa) at 45 °C - 55 °C to obtain 610 g of cinacalcet II with a yield of 100%.

[0061] The above 610 g of cinacalcet II was added to 1.8 L of acetonitrile. Stirring was initiated, and 148 ml of commercially available concentrated hydrochloric acid (12 mol / L) was added at room temperature. The mixture was stirred for 1 - 3 hours, 5.4 L of water was added, and it was stirred at room temperature (30 °C) for 12 - 15 hours. Then it was filtered, and the filter cake was dried under vacuum at 45 °C - 55 °C for 12 - 16 hours to obtain 515 g of cinacalcet hydrochloride III with an HPLC purity of 99.5%, the maximum single impurity of 0.03%, and a yield of 80.9% (calculated based on Compound I).

[0062] Example 3

[0063] Compound I (900 g, 2.42 mol) was added to 4.5 L of tetrahydrofuran. Stirring was started, and the temperature was lowered to 0 - 10°C. 138 g of sodium borohydride (3.63 mol) was added, and 1017 g of a 50% by mass boron trifluoride tetrahydrofuran solution (3.63 mol) (the mass percentage refers to the mass of boron trifluoride accounting for the total mass of the boron trifluoride tetrahydrofuran solution) was added dropwise. After the dropwise addition, the mixture was stirred at 0 - 10°C for 1 h, then heated to 60 - 70°C and kept reacting for 5 h. When the content of the raw material (Compound I) monitored by HPLC was less than 1%, the reaction was stopped. It was cooled to room temperature (30 - 35°C), 2.7 L of ethyl acetate was added to dilute the reaction solution, and 4.19 Kg of MgSO4·7H2O (magnesium sulfate heptahydrate, 17.0 mol) was slowly added in batches at 30 - 35°C to quench the reaction. The quenching process was very mild. After the addition was completed, the temperature was raised to 70 - 75°C and stirred for 3 - 4 h, then cooled to room temperature (20°C), filtered. The organic phase was adjusted to pH = 8 - 9 with an aqueous sodium hydroxide solution (2 mol / L), extracted twice with ethyl acetate, the organic phases were combined, washed with water, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum (-0.08 MPa - -0.1 MPa) at 45°C - 55°C to obtain 905 g of cinacalcet II with a yield of 100%.

[0064] The above 905 g of cinacalcet II was added to 2.7 L of acetonitrile. Stirring was started, and 223 ml of commercially available concentrated hydrochloric acid (12 mol / L) was added at room temperature. The mixture was stirred for 1 - 3 h, 8.1 L of water was added thereto, and the mixture was stirred at room temperature (25°C) for 12 - 15 h, then filtered. The filter cake was dried under vacuum at 45°C - 55°C for 12 h - 16 h to obtain 766 g of cinacalcet hydrochloride III with an HPLC purity of 99.4%, a maximum single impurity of 0.03%, and a yield of 80.2% (calculated based on Compound I).

[0065] Comparative Example 1 (method referring to the patent specification CN201210577243)

[0066] Compound I (20 g, 0.054 mol) was added to 4400 ml of tetrahydrofuran. Stirring was started, and the temperature was lowered to 0 - 5 °C. 6.0 g of sodium borohydride (0.075 mol) was added, and 22.9 g of boron trifluoride tetrahydrofuran with a mass percentage of 50% (0.075 mol) (the mass percentage refers to the mass of boron trifluoride accounting for the total mass of the boron trifluoride tetrahydrofuran solution) was added dropwise. After the dropwise addition, the temperature was raised to 60 - 70 °C and the mixture was kept warm and reacted for 3 hours. It was cooled to room temperature (0 - 5 °C), and 1 mol / L hydrochloric acid aqueous solution was added to adjust the pH to 2 - 3. (During the addition process, a large amount of heat was released violently. Excessive sodium borohydride reacted with water to generate a large amount of hydrogen gas, resulting in material overflow. At the same time, hydrochloric acid reacted with excessive boron trifluoride complex to generate a large amount of hydrogen fluoride gas, which has a strong irritating and corrosive effect on the respiratory mucosa and skin and is likely to cause skeletal and dental deformities.) After the addition was completed, the temperature was raised to 65 °C and refluxed for 1 hour. The organic phase was adjusted to pH = 8 - 9 with 2 mol / L sodium hydroxide aqueous solution, extracted twice with ethyl acetate, the organic phases were combined, washed with water and brine, and the filtrate was concentrated to dryness under vacuum (-0.08 MPa - -0.1 MPa) at 45 °C - 55 °C to obtain 20 g of cinacalcet II, with a yield of 100%.

[0067] The above 20 g of cinacalcet II was added to 60 ml of acetonitrile. Stirring was started, and 5 ml of commercially available concentrated hydrochloric acid was added at room temperature. Stirring was carried out for 1 - 3 hours, 180 mL of water was added thereto, and stirring was carried out at room temperature for 12 - 15 hours. Filtration was carried out, and the filter cake was dried under vacuum at 50 °C for 20 - 24 hours to obtain 12.7 g of cinacalcet hydrochloride III, with an HPLC purity of 98.7%, the maximum single impurity of 0.50%, and a yield of 59.9% (calculated based on compound I).

[0068] Comparative Example 2 (referring to the method in Patent Specification WO2007127445)

[0069] Compound I (5.0 g, 0.0135 mol) was added to 150 ml of tetrahydrofuran. Stirring was started, and the temperature was lowered to 0 - 5 °C. 10.3 g of boron trifluoride tetrahydrofuran with a mass percentage of 50% (0.034 mol) (the said mass percentage refers to the mass of boron trifluoride accounting for the total mass of the boron trifluoride tetrahydrofuran solution) was added dropwise. After the dropwise addition, the temperature was raised to 20 - 30 °C and the mixture was kept warm and reacted for 16 hours. It was cooled to room temperature (0 - 5 °C), 6 mol / L hydrochloric acid aqueous solution was added to adjust the pH to 2 - 3. After the addition, the temperature was raised to 65 °C and refluxed for 1 hour. The organic phase was adjusted to pH = 8 - 9 with 2 mol / L sodium hydroxide aqueous solution, extracted twice with ethyl acetate, the organic phases were combined, washed with water and then with brine. The filtrate was concentrated to dryness under vacuum (-0.08 MPa - -0.1 MPa) at 45 °C - 55 °C and then purified by column chromatography. The mobile phase was dichloromethane:methanol = 97.5:2.5 - 95:5, and 3.3 g of cinacalcet II was obtained with a yield of 68.6%.

[0070] The above 3.3 g of cinacalcet II was added to 10 ml of acetonitrile. Stirring was started, 1 ml of commercially available concentrated hydrochloric acid was added at room temperature, and the mixture was stirred for 1 - 3 hours. 30 mL of water was added thereto, and the mixture was stirred at room temperature for 12 - 15 hours. It was filtered, and the filter cake was dried under vacuum at 50 °C for 20 - 24 hours to obtain 2.73 g of cinacalcet II hydrochloride. HPLC purity: 98.9%, maximum single impurity 0.32%, total yield 51.5% (calculated based on compound I).

Claims

1. A preparation method of cinacalcet II, characterized in that It includes the following steps: In a solvent, a reduction reaction is carried out between Compound I and a reducing agent. After the reaction is completed, the reaction is quenched with a metal hydrosulfate to obtain cinacalcet II. The reducing agent is a system of alkali metal borohydride and boron trifluoride. The general structural formula of the metal hydrosulfate is M x (SO4) y ·zH2O, where M is one or more of metal ions in the first, second, third, and fourth periods of the periodic table and ammonium ion, x is 1 to 2, y is 1 to 3, and z is 0 to 20; 2. The preparation method of cinacalcet II as claimed in claim 1, characterized in that: In the preparation method of cinacalcet II, the "metal ions of the first, second, third, and fourth periods in the periodic table" are alkali metal ions, alkaline earth metal ions, and group IIIA metal ions of the first, second, third, and fourth periods in the periodic table; and / or In the method for preparing cinacalcet II described above, the M x (SO4) y is M2SO4, MSO4, M(SO4)2 or M2(SO4)3.

3. The preparation method of cinacalcet II as claimed in claim 2, characterized in that: In the preparation method of cinacalcet II, the "alkali metal ions of the first, second, third, and fourth periods in the periodic table" are sodium ions, potassium ions, or lithium ions; and / or In the preparation method of cinacalcet II, the "alkaline earth metal ions of the first, second, third, and fourth periods in the periodic table" are magnesium ions; and / or In the preparation method of cinacalcet II, the "group IIIA metal ions of the first, second, third, and fourth periods in the periodic table" are aluminum ions; and / or The MSO4 is MgSO4; and / or The M2SO4 is K2SO4 and / or Na2SO4; and / or The M(SO4)2 is KAl(SO4)2, NaAl(SO4)2, NH4Al(SO4)2, (NH4)2Fe(SO4)2, or (NH4)2Cu(SO4)2; and / or The M2(SO4)3 is Al2(SO4)3, Na2Fe2(SO4)3, Na2Ni2(SO4)3, or Na2Mn2(SO4)3.

4. The preparation method of cinacalcet II as claimed in claim 3, characterized in that: The described M x (SO4) y ·zH2O is Na2SO4·10H2O, KAl(SO4)2·12H2O or MgSO4·7H2O.

5. The preparation method of cinacalcet II as claimed in claim 1, characterized in that: In the preparation method of cinacalcet II, the molar ratio of the hydrated metal sulfate to the compound I is 1 to 20; and / or In the preparation method of cinacalcet II, the temperature of the "quenching reaction" is 5°C to 40°C; and / or In the preparation method of cinacalcet II, the time of the "quenching reaction" is 1 hour to 12 hours; and / or The preparation method of cinacalcet II adopts the following post-treatment steps: after the quenching reaction, stir, filter, adjust the pH to 8 - 9, extract, wash, dry, filter, and concentrate to obtain cinacalcet II.

6. The preparation method of cinacalcet II as claimed in claim 5, characterized in that: In the method for preparing cinacalcet II, the metal hydrosulfate is combined with the The amount of compound I The molar ratio is 2 to 15; and / or In the preparation method of cinacalcet II, the temperature of the "quenching reaction" is 10°C to 35°C and / or In the preparation method of cinacalcet II, the time of the "quenching reaction" is 3 hours to 8 hours.

7. The preparation method of cinacalcet II as claimed in claim 6, characterized in that: In the preparation method of cinacalcet II, the molar ratio of the hydrated metal sulfate to the compound I is 3, 5, or 7; and / or In the preparation method of cinacalcet II described above, the temperature of the "quenching reaction" is 10°C to 15°C, 20°C to 25°C, or 30°C to 35°C; and / or, In the preparation method of cinacalcet II described above, the time of the "quenching reaction" is 3 hours to 4 hours, 5 hours to 6 hours, or 7 hours to 8 hours.

8. The preparation method of cinacalcet II according to claim 1, wherein: In the preparation method of cinacalcet II described above, the alkali metal borohydride is sodium borohydride and / or potassium borohydride; and / or, In the preparation method of cinacalcet II described above, the ratio of y to x is 0.5 to 3; and / or, In the preparation method of cinacalcet II described above, z is 5 to 15; and / or, In the preparation method of cinacalcet II described above, the solvent is an ether solvent; and / or, In the preparation method of cinacalcet II described above, the volume-mass ratio of the solvent to compound I The product quality ratio is 1 mL / g to 10 mL / g; and / or, In the preparation method of cinacalcet II described above, in the "alkali metal borohydride and boron trifluoride system", the molar ratio of the alkali metal borohydride to boron trifluoride is 1; and / or, In the preparation method of cinacalcet II described above, the molar ratio of the reducing agent to compound I is 1 to 5; and / or, In the preparation method of cinacalcet II described above, the temperature of the reduction reaction is 0 to 100°C; and / or, In the preparation method of cinacalcet II described above, the time of the reduction reaction is 1 hour to 10 hours; and / or, In the preparation method of cinacalcet II described above, the reduction reaction is carried out by the following steps: adding an alkali metal borohydride to a mixture formed by compound I and a solvent, then adding boron trifluoride, stirring, heating to continue the reaction, after the reaction is completed, cooling, and quenching the reaction to obtain cinacalcet II.

9. The preparation method of cinacalcet II according to claim 9, wherein: In the preparation method of cinacalcet II described above, the ratio of y to x is 0.5, 1.0, 1.5, 2.0, or 3.0; and / or, In the preparation method of cinacalcet II described above, z is 7, 10, or 12; and / or, In the preparation method of cinacalcet II described above, the ether solvent is tetrahydrofuran; and / or, In the method for preparing cinacalcet II, the volume of the solvent and the compound I The volume-mass ratio is 3 mL / g to 8 mL / g; and / or In the preparation method of cinacalcet II described above, the molar ratio of the reducing agent to compound I is 1.5 to 3; and / or, In the preparation method of cinacalcet II described above, the temperature of the reduction reaction is 50°C to 80°C; and / or, In the preparation method of cinacalcet II described above, the time of the reduction reaction is 3 hours to 8 hours.

10. A preparation method of cinacalcet hydrochloride III, characterized in that It comprises the following steps: After obtaining cinacalcet II according to the method described in any one of claims 1-9, reacting cinacalcet II with hydrochloric acid to form a salt to obtain cinacalcet hydrochloride III.

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