Preparation method of high purity cinacalcet hydrochloride

Abstract

The invention discloses a preparation method of high-purity cinacalcet hydrochloride. The preparation method of the high-purity cinacalcet hydrochloride comprises the following steps: performing an alkylation reaction of 3-(3-(trifluoromethyl)phenyl) propyl ester with (R)-1-(naphthyl-1-yl) ethylamine salt in the presence of a solvent and an acid-binding agent, and performing salt forming to obtain the cinacalcet hydrochloride with the purity of more than or equal to 99.5%. The (R)-1-(naphthyl-1-yl) ethylamine salt is (R)-1-(naphthyl-1-yl) ethylamine hydrochloride or (R)-1-(naphthyl-1-yl) ethylamine sulphate, the solvent is a mixed solvent of water and an aprotic organic solvent, and the aprotic organic solvent is methylbenzene or dimethylbenzene. The volume of water is 5-90% of that of the aprotic organic solvent, the weight of the aprotic organic solvent is 1-10 times that of the 3-(3-(trifluoromethyl) phenyl) propyl ester. The high-purity cinacalcet hydrochloride with the purity of more than or equal to 99.5% can be finally obtained according to the method disclosed by the invention. The method is simple in operation and applicable to the industry.

Description

technical field

[0001] The invention belongs to the technical field of medicine preparation, and in particular relates to a preparation method of high-purity cinacalcet hydrochloride. Background technique

[0002] Cinacalcet hydrochloride is a calcimimetics developed by NPS Pharmaceuticals in the United States. It can activate the calcium receptor in the parathyroid gland, thereby reducing the secretion of parathyroid hormone (PTH), regulate the behavior of the calcium receptor of the parathyroid gland, and reduce the thyroid gland by enhancing the sensitivity of the receptor to the calcium level in the blood stream. Levels of parathyroid hormone, calcium, phosphorus, and calcium-phosphorus complex. It is mainly used for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease (CKD) on dialysis and hypercalcemia in patients with parathyroid carcinoma.

[0003] The chemical name of cinacalcet hydrochloride is: (R)-N-(1-(naphthalen-1-yl)ethyl)-3...

Examples

Embodiment 1）

[0021] The preparation method of the high-purity cinacalcet hydrochloride of the present embodiment is as follows:

[0022] First add 1L of toluene (866g) and 0.2L of deionized water into the four-necked flask, then add 228.5g of naphthylethylamine hydrochloride (1.1mol) and 207.3g of diisopropylethylamine ( 1.6mol) and 282.3g of 3-(3-(trifluoromethyl)phenyl)propyl methanesulfonate (1.0mol), under the protection of nitrogen, heated to reflux reaction, sampling in the control, until the end of the reaction (about 24h).

[0023] After the reaction, stop heating, let stand, separate the liquid, discard the water phase; add 1500mL of 1mol / L dilute hydrochloric acid to the organic phase, stir, stand still, separate the liquid, discard the water phase; slowly cool the organic phase to 0-5 ℃, precipitated white crystals, filtered with suction, washed the filter cake with 100mL of cold toluene (0-5 ℃), and dried in a vacuum oven to obtain 280.1g of an off-white solid with a yield of ...

Embodiment 2～ Embodiment 4）

[0025] Each embodiment is basically the same as Embodiment 1, and the differences are shown in Table 1.

[0026] Table 1

[0027] Example 1 Example 2 Example 3 Example 4 Aprotic organic solvents toluene methyl tert-butyl ether Xylene Methyltetrahydrofuran Naphthalene ethylamine salt Naphthalene ethylamine hydrochloride Naphthalene ethylamine tartrate Naphthalene ethylamine sulfate naphthalene ethylamine mandelate product weight 280.1g 275.1g 283.1g 270.7g yield 71.2% 69.9% 71.9% 68.8% purity 99.62% 99.55% 99.61% 99.53% By-product I 0.31% 0.35% 0.32% 0.36% By-product II 0.03% 0.07% 0.04% 0.08%

Embodiment 5～ Embodiment 8）

[0029] Each embodiment is basically the same as Embodiment 1, and the differences are shown in Table 2.

[0030] Table 2

[0031] Example 1 Example 5 Example 6 Example 7 Example 8 water 0.2L 0.5L 0.1L 0.6L 0.3L toluene 1L 1L 1L 3L 1.5L product weight 280.1g 276.8g 279.3g 273.5g 282.7g yield 71.2% 70.3% 71.0% 69.5% 71.8% purity 99.62% 99.52% 99.63% 99.56% 99.60% By-product I 0.31% 0.33% 0.30% 0.32% 0.33% By-product II 0.03% 0.12% 0.04% 0.09% 0.04%

technical field

[0001] The invention belongs to the technical field of medicine preparation, and in particular relates to a preparation method of high-purity cinacalcet hydrochloride. Background technique

[0002] Cinacalcet hydrochloride is a calcimimetics developed by NPS Pharmaceuticals in the United States. It can activate the calcium receptor in the parathyroid gland, thereby reducing the secretion of parathyroid hormone (PTH), regulate the behavior of the calcium receptor of the parathyroid gland, and reduce the thyroid gland by enhancing the sensitivity of the receptor to the calcium level in the blood stream. Levels of parathyroid hormone, calcium, phosphorus, and calcium-phosphorus complex. It is mainly used for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease (CKD) on dialysis and hypercalcemia in patients with parathyroid carcinoma.

[0003] The chemical name of cinacalcet hydrochloride is: (R)-N-(1-(naphthalen-1-yl)ethyl)-3...

Examples

Embodiment 1）

[0021] The preparation method of the high-purity cinacalcet hydrochloride of the present embodiment is as follows:

[0022] First add 1L of toluene (866g) and 0.2L of deionized water into the four-necked flask, then add 228.5g of naphthylethylamine hydrochloride (1.1mol) and 207.3g of diisopropylethylamine ( 1.6mol) and 282.3g of 3-(3-(trifluoromethyl)phenyl)propyl methanesulfonate (1.0mol), under the protection of nitrogen, heated to reflux reaction, sampling in the control, until the end of the reaction (about 24h).

[0023] After the reaction, stop heating, let stand, separate the liquid, discard the water phase; add 1500mL of 1mol / L dilute hydrochloric acid to the organic phase, stir, stand still, separate the liquid, discard the water phase; slowly cool the organic phase to 0-5 ℃, precipitated white crystals, filtered with suction, washed the filter cake with 100mL of cold toluene (0-5 ℃), and dried in a vacuum oven to obtain 280.1g of an off-white solid with a yield of ...

Embodiment 2～ Embodiment 4）

[0025] Each embodiment is basically the same as Embodiment 1, and the differences are shown in Table 1.

[0026] Table 1

[0027] Example 1 Example 2 Example 3 Example 4 Aprotic organic solvents toluene methyl tert-butyl ether Xylene Methyltetrahydrofuran Naphthalene ethylamine salt Naphthalene ethylamine hydrochloride Naphthalene ethylamine tartrate Naphthalene ethylamine sulfate naphthalene ethylamine mandelate product weight 280.1g 275.1g 283.1g 270.7g yield 71.2% 69.9% 71.9% 68.8% purity 99.62% 99.55% 99.61% 99.53% By-product I 0.31% 0.35% 0.32% 0.36% By-product II 0.03% 0.07% 0.04% 0.08%

Embodiment 5～ Embodiment 8）

[0029] Each embodiment is basically the same as Embodiment 1, and the differences are shown in Table 2.

[0030] Table 2

[0031] Example 1 Example 5 Example 6 Example 7 Example 8 water 0.2L 0.5L 0.1L 0.6L 0.3L toluene 1L 1L 1L 3L 1.5L product weight 280.1g 276.8g 279.3g 273.5g 282.7g yield 71.2% 70.3% 71.0% 69.5% 71.8% purity 99.62% 99.52% 99.63% 99.56% 99.60% By-product I 0.31% 0.33% 0.30% 0.32% 0.33% By-product II 0.03% 0.12% 0.04% 0.09% 0.04%

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