Preparation method of cinacalcet hydrochloride defluorination impurity compound
A technology of cinacalcet hydrochloride and a compound is applied in the field of preparation of defluorinated impurity compounds of cinacalcet hydrochloride, which can solve the problems of difficult preparation of TMSCF2H, side reactions of difluorocarbene, no trifluoromethyl compound, etc. The effect of low material cost, promotion of quality control, and cost reduction
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Embodiment 1
[0043] a. Add the intermediate of 10g cinacalcet hydrochloride (N-((1 R )-1-(1-naphthyl)ethyl)-3-(3-(trifluoromethyl)phenyl)propionamide), 80g tetrahydrofuran, cooled to 0-5°C in an ice bath protected by nitrogen. 9.1gLiAlH4 was added slowly, and the temperature was raised to reflux for 72 hours.
[0044] b. Cool down to 5-15°C, add 100g of ice water bath to quench, after addition, keep stirring in ice bath for 1h. Filtrate, wash with 20 g of methyl tert-butyl ether, and separate the layers. Add 20 g of methyl tert-butyl ether to the aqueous layer for washing, separate the layers, combine the organic layers and concentrate to dryness under reduced pressure at 40° C. to obtain a crude light brown oily product.
[0045] c. Separation by column chromatography, the eluent is ethyl acetate: n-ethane = 1:8, and 0.8 g of oily substance is obtained.
[0046] d. Add 10g of tertiary methyl ether to dissolve, add dropwise 0.3g of hydrochloric acid, the solid precipitates out, filters, ...
Embodiment 2
[0048] a. Add the intermediate of 8g cinacalcet hydrochloride (N-((1 R )-1-(1-naphthyl)ethyl)-3-(3-(trifluoromethyl)phenyl)propionamide), 100g 2-methyltetrahydrofuran, cooled to 0-5°C in an ice bath protected by nitrogen. 10.0 g of potassium aluminum hydride was slowly added, and the temperature was raised to reflux for 64 hours.
[0049] b. Cool down to 5-15°C, add 100g of ice water bath to quench, after addition, keep stirring in ice bath for 1h. filter, 16g
[0050] Wash with methyl tert-butyl ether, separate layers, add 16 g of methyl tert-butyl ether to the aqueous layer, wash, separate layers, combine organic layers and concentrate to dryness under reduced pressure at 40°C to obtain crude light brown oily product.
[0051] c. Separation by column chromatography, the eluent is ethyl acetate: n-ethane = 1:10, and 0.6 g of oily substance is obtained.
[0052] d. Add 10 g of tertiary methyl ether to dissolve, add dropwise 0.25 g of sulfuric acid, the solid precipitates, f...
Embodiment 3
[0054] a. Add the intermediate of 10g cinacalcet hydrochloride (N-((1 R )-1-(1-naphthyl)ethyl)-3-(3-(trifluoromethyl)phenyl)propionamide), 100g dichloromethane, cooled to 0-5°C in an ice bath protected by nitrogen. Slowly add 15.0 g of dihydro-bis(2-methoxyethoxy)sodium aluminate, and heat up to reflux for 70 hours.
[0055] b. Cool down to 5-15°C, quench by adding 100 g of iced acetic acid aqueous solution, and keep stirring in the ice bath for 1 h after the addition is complete. Filtrate, wash with 20 g of methyl tert-butyl ether, and separate the layers. Add 20 g of methyl tert-butyl ether to the aqueous layer for washing, separate the layers, combine the organic layers and concentrate to dryness under reduced pressure at 40° C. to obtain a crude light brown oily product.
[0056] c. Separation by column chromatography, the eluent is ethyl acetate: n-heptane = 1:8, and 0.9 g of oily substance is obtained.
[0057] d. Add 10 g of tertiary methyl ether to dissolve, add drop...
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