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Cinacalcet hydrochloride preparation method

A technology of cinacalcet hydrochloride and dilute hydrochloric acid, which is applied in the field of organic synthesis route design and the preparation of raw materials and intermediates, can solve the problems of difficult post-processing, complicated process operation, incomplete reaction, etc., and promote economic and technological development , The process is simple and the effect of industrialization is realized

Inactive Publication Date: 2019-06-25
ZHEJIANG WAN SHENG PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0028] Through the investigation and analysis of the literature on the synthesis route of cinacalcet hydrochloride, it can be seen that the starting material trifluoromethylphenylpropionaldehyde in the synthesis route 1 is not easy to obtain, and the Ti(o-i-pr) used in the condensation reaction 4 Post-processing is very difficult in the industrial production process, and the anhydrous requirement is high. In the reaction, the highly toxic sodium cyanoborohydride is used to reduce the unsaturated double bond, which is not conducive to large-scale production; the entire reaction route design in the synthesis route 2 is reasonable, but According to the literature, the process still has the disadvantages of incomplete reaction, low yield, low purity of the finished product, and more cumbersome waste water and residue after post-treatment, which is not suitable for industrial production and does not conform to the concept of green chemistry; the third synthesis route uses DCC for condensation, The by-products of DCC are difficult to remove, and the dangerous lithium aluminum hydride is used in the process, which is not conducive to industrial production; the synthetic route 4 process operation is more complicated, and the dangerous borane dimethyl sulfide is used in the process, which is not conducive to industrial production. Synthetic route five adopts racemic starting material 1-naphthylethanone to synthesize racemic cinacalcet, and then split to obtain cinacalcet of R configuration, which has higher cost and is uneconomical

Method used

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  • Cinacalcet hydrochloride preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Embodiment 1: the preparation of sulfonation reaction intermediate I

[0060]

[0061] Put 300g of 3-(3-trifluoromethylphenyl)propanol, 1800ml of toluene, and 246ml of triethylamine into a 5L three-neck flask, protect it with inert gas, stir, and cool the system down to -5~0°C. Control the temperature from -5 to 0°C, and add 127.7ml of MsCl dropwise. After about 2 hours of dripping, keep stirring at -5~0°C for 1 hour, raise the temperature of the reaction system to 20~30°C for 3 hours, and monitor the reaction by TLC (developing agent: petroleum ether: ethyl acetate = 1:1 (volume ratio)) completely. Cool the system down to 5-10°C, control the system temperature to ≤20°C, add 740ml of water, stir, the solids in the system dissolve, separate the liquids, add 250ml of 0.2mol / L HCl to the organic phase for extraction, and then use 740ml of HCl to extract the organic phase 2 O×3 washing (removal of triethylamine hydrochloride), separation of the organic phase, (bath tem...

Embodiment 2

[0062] Embodiment 2: the preparation of cinacalcet base

[0063]

[0064] Add 425g of Intermediate I, 269.4g of (R)-(+)-1-(1-naphthyl)ethylamine, 395.3g of potassium carbonate, and 3L of acetonitrile into a 5L three-necked flask, stir, and heat to reflux (80-83°C ), reflux for 16 to 17 hours, lower the temperature to 65 to 70°C, add 197g of potassium carbonate to the reaction system, heat to reflux, continue to stir and react for 7 to 8 hours, lower the temperature of the reaction system to 25±5°C, filter, and filter the cake Wash with 2L of acetonitrile, combine the filtrate, concentrate the filtrate to dryness under reduced pressure, add 2075ml of dichloromethane to the residue, stir to dissolve completely, then extract with 1200ml of 5% HCl, and use 2×1200ml NaHCO for the organic phase in turn 3 The saturated solution was washed with 1200ml of water, and the organic phase was concentrated to dryness under reduced pressure to obtain 493g of cinacalcet base, with a yield o...

Embodiment 3

[0065] Embodiment 3: Salt-forming reaction, preparation of cinacalcet hydrochloride crude product

[0066]

[0067] Add 493g of cinacalcet base and 493ml of acetonitrile into a 5L three-necked flask, stir to dissolve, and add 4930ml of 1mol / L HCl dropwise at a temperature of 55±5°C. The dropwise addition is completed in about 30 minutes, and a large amount of solids gradually precipitate out during the process. Continue to stir at room temperature (25±5°C) to form salt for 2 hours, lower the temperature of the system to 0-10°C, crystallize for 1-2 hours, filter, wash the filter cake with water, and dry it in a blast oven at 50°C to obtain 503.8g of carbamide hydrochloride. The crude product of Nakasai has a yield of 92.7%.

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Abstract

The invention provides a cinacalcet hydrochloride preparation method, wherein the cinacalcet hydrochloride finished product is obtained by using 3-(3-trifluoromethylphenyl)propanol and (R)-(+)-1-(1-naphthyl)ethylamine as starting raw materials through two-step chemical reaction, one-step salt formation and two-step purification. According to the present invention, the method has characteristics ofsimple process, easily-available raw materials, economy and environmental protection, easily achieves industrialization, and can promote the economic and technological development of cinacalcet hydrochloride bulk drugs.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and in particular relates to a therapeutic drug, Cinnamate hydrochloride, used for treating secondary hyperparathyroidism in chronic kidney disease (CKD) maintenance dialysis patients Method for the preparation of Kasai. Background technique [0002] Secondary hyperparathyroidism (SHPT) is a common complication in patients with chronic renal failure, and it is also one of the most important and serious complications in end-stage chronic renal failure hemodialysis. Its main manifestations are elevated levels of parathyroid hormone (PTH) and parathyroid hyperplasia, which can lead to severe bone damage, refractory skin itching, anemia, nervous system damage, and cardiovascular disease. Studies have shown that long-term high levels of PTH can increase the risk of death in patients with chronic kidney disease requiring long-te...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C209/16C07C209/00C07C209/84C07C211/30
Inventor 马猛单瑞平迟宗良何俊叶锐
Owner ZHEJIANG WAN SHENG PHARMA CO LTD
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