Preparation method of cinacalcet hydrochloride and intermediate thereof

A technology of cinacalcet hydrochloride and cinacalcet, which is applied in the field of preparation of cinacalcet hydrochloride and its intermediates, can solve the problems of unsuitability for industrial production, low product purity, long route and the like

Active Publication Date: 2020-05-26
SHANGHAI BOCIMED PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The technical problem to be solved by the present invention is to overcome the preparation method route of cinacalcet hydrochloride in the prior art is long, yield is low, optical purity is low, obtains The product has low purity, does not meet the requirements of raw materials, is not suitable for industrial production and other defects, and provides a preparation method of cinacalcet hydrochloride and its intermediates

Method used

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  • Preparation method of cinacalcet hydrochloride and intermediate thereof
  • Preparation method of cinacalcet hydrochloride and intermediate thereof
  • Preparation method of cinacalcet hydrochloride and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Example 1: Preparation of Cinacalcet Hydrochloride Intermediate II (refer to the method of Synthetic Route 1 in the specification of patent CN200980136709.1)

[0063]

[0064] Under the protection of nitrogen, add 100 g (0.587 mol) of 1-naphthyl ethyl ketone and 100 g (0.492 mol) of 3-trifluoromethylamphetamine into 700 mL of ethanol, then add 0.48 g (0.00499 mol) of methanesulfonic acid, and heat to 60-65 Stir at ℃ for 3-4 hours, then concentrate in vacuo (-0.085MPa--0.1MPa, 45-55℃) to remove the solvent. Add 350mL of n-heptane, stir at 15-20°C for 1-2 hours, discard the supernatant after standing and repeat three times; vacuum concentration (-0.085MPa~-0.1MPa, 45-55°C) to obtain cinacalcet Intermediate II 161.0g, yield 92.05%, HPLC purity 98.37%.

Embodiment 2

[0065] Embodiment 2: the preparation of L-cinacalcet III tartrate

[0066]

[0067] Add 20 g (0.0563 mol) of cinacalcet intermediate II, 27 mg (0.0000576 mol) of bis(1,5-cyclooctadiene)-rhodium trifluoromethanesulfonate, (S)-3,3' to the hydrogenation kettle - Bis(2,4,6-triisopropylphenyl)-1,1'-di-2-naphthol cyclic phosphate (L*) 44 mg (0.0000584 mol) and ethanol 100 mL. Hydrogenation is carried out at a hydrogen pressure of 4-6 atmospheres and 40-50° C. for 2.5-3.5 hours.

[0068] Cool, filter, wash with ethanol and concentrate in vacuo (45°C~55°C, -0.085MPa~-0.1MPa) to remove the solvent to obtain crude cinacalcet IV. Then, 70 mL of isopropyl acetate was added, stirred and filtered, and a solution of 8.45 g of L-tartaric acid in 70 mL of ethanol was added to the filtrate. Heat to 60℃~65℃ and stir for 0.5 hours, cool to 5℃~10℃ and stir for 1~2 hours, filter, wash once with isopropyl acetate, vacuum dry (45℃~55℃, -0.01MPa~-0.1MPa ) in 12 to 16 hours to obtain an off-white...

Embodiment 3

[0069] Embodiment 3: the preparation of L-cinacalcet III tartrate

[0070]

[0071] Add 60 g (0.169 mol) of cinacalcet intermediate II, 40 mg (0.0000854 mol) of bis(1,5-cyclooctadiene)-rhodium trifluoromethanesulfonate, (S)-3,3' to the hydrogenation kettle - Bis(2,4,6-triisopropylphenyl)-1,1'-di-2-naphthol cyclic phosphate (L*) 65 mg (0.0000863 mol) and ethanol 180 mL. Hydrogenation was carried out at a hydrogen pressure of 6-8 atmospheres and 30-40° C. for 3.5-4.5 hours.

[0072] Cool, filter, wash with ethanol and concentrate in vacuo (45°C~55°C, -0.085MPa~-0.1MPa) to remove the solvent to obtain crude cinacalcet IV. Add 210 mL of isopropyl acetate, stir and filter, then add a solution of 25.4 g of L-tartaric acid in 210 mL of ethanol to the filtrate. Heat to 60℃~65℃ and stir for 0.5 hours, cool to 5℃~10℃ and stir for 1~2 hours, filter, wash once with isopropyl acetate, vacuum dry (45℃~55℃, -0.01MPa~-0.1MPa ) in 12 to 16 hours to obtain an off-white solid which was L-c...

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Abstract

The invention discloses a preparation method of cinacalcet hydrochloride and an intermediate thereof. The invention provides a preparation method of an intermediate L-cinacalcet tartrate III of cinacalcet hydrochloride. The method comprises the following steps: step (1): in an organic solvent, in the presence of a chiral catalyst and a chiral ligand, an asymmetric hydrogenation reduction reactionis conducted on a cinacalcet intermediate II to obtain cinacalcet IV, wherein the chiral catalyst is bis (1, 5-cyclooctadiene)-rhodium trifluoromethanesulfonate, and the chiral ligand is (S)-3, 3'-bis(2, 4, 6-triisopropylphenyl)-1, 1'-di-2-naphthol cyclic phosphate; and (2) in an organic solvent, a neutralization reaction is conducted between cinacalcet IV and L-tartaric acid to obtain L-cinacalcet tartrate III. The preparation method disclosed by the invention has advantages of short route step, simple and safe operation and high total yield; and the prepared product has high purity, meets the requirements of bulk drugs, is low in production cost and is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of cinacalcet hydrochloride and an intermediate thereof. Background technique [0002] Cinacalcet Hydrochloride (I), the first drug in a new class of compounds known as calcimimetics, activates calcium receptors in the parathyroid glands, thereby reducing parathyroid hormone secretion. This product can regulate the behavior of parathyroid calcium receptors, reduce the levels of parathyroid hormone, calcium, phosphorus and calcium-phosphorus complexes by enhancing the sensitivity of the receptors to calcium levels in the blood stream. Cinacalcet hydrochloride was developed by NPS Pharmaceuticals of the United States, and on March 8, 2004, the FDA approved cinacalcet hydrochloride to be on the market, with a trade name of Sensipar and a specification of 25 mg or 75 mg). [0003] [0004] Cinacalcet hydrochloride is used for the treatment of secondary hyperparathyroidism in patients with chronic kidney dis...

Claims

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Application Information

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IPC IPC(8): C07C209/00C07C211/30C07C51/41C07C59/255
CPCC07C209/00C07C51/412C07C209/52C07C249/02C07B2200/07C07C211/30C07C59/255C07C251/24
Inventor 陈健于冲冲王婷婷应述欢
Owner SHANGHAI BOCIMED PHARMA CO LTD
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