Synthesis method of cinacalcet

Abstract

The invention discloses a synthesis method of cinacalcet. The synthetic route is divided into two parts, namely, (1) preparing a chiral compound as shown in the description from racemic 1-naphthylethylamine as a starting material by virtue of a dynamic kinetic reliquid method in the presence of Pd/LDH-SA serving as a racemic catalyst, p-chlorophenol fatty acyl ester serving as an acyl donor and lipase serving as a biological reliquid catalyst; and (2) reacting m-trifluoromethylbenzaldehyde serving as a starting material and a cheap and easily available material acetaldehyde to obtain m-trifluoromethyl cinnamic aldehyde and carrying out reduced pressure distillation to obtain a pure product; reacting m-trifluoromethyl cinnamic aldehyde and the compound as shown in the description to produce an imine intermediate; dissolving the imine intermediate in ethanol and reacting in the presence of Raney nickel serving as a hydrogenation catalyst to obtain the product cinacalcet. By the synthesis method, the reaction yield and the optical purity of the product are increased, the reaction conditions are milder and the raw materials are easily available.

Description

technical field [0001] The invention belongs to the field of drug synthesis research, in particular to a new preparation route of cinacalcet. Background technique [0002] Cinacalcet hydrochloride (cinacalcet hydrochloride), the chemical name is (R)-α-methyl-N-[3-[3-(trifluoromethyl)-phenyl]propyl]-1-naphthylmethylamine salt salt. [0003] Its structural formula is [0004] [0005] Its molecular formula is C 22 h 23 f 3 NCl, molecular weight 393.8. [0006] Cinacalcet hydrochloride is a calcimimetic agent developed by NPS Pharmaceuticals in the United States. It was first launched in the United States in 2004. It is clinically used to treat secondary hyperparathyroidism and parathyroid tumors caused by chronic kidney disease receiving dialysis. patients with hypercalcemia. This product can inhibit the secretion of parathyroid hormone by activating calcium ion receptors. It is well absorbed in the body and has good bioavailability (about 80%). It reaches the maximu...

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Problems solved by technology

Each route has different disadvantages: wherein route one adopts direct condensation of amine and aldehyde to generate imine, and then reduces to obtain product, which has advantages such as short route, but m-trifluoromethamphetamine is difficult to prepare, and in the process of reduction , using the relatively expensive reducing agent sodium cyanoborohydride, the most important thing is that the final prepared racemized product needs to be further resolved, so the synthetic route that advances the resolution steps has an advantage; route 2 is in route 1 On the basis of R-type naphthalene ethylamine instead of m-trifluoromethyl amphetamine, m-trifluoromethyl phenylpropionaldehyde instead of naphthalene ethyl ketone, on the basis of retaining the advantages of route one, the product prepared does not need further However, it is difficult to prepare the raw material m-trifluoromethylphenylpropionaldehyde, and the condensation into imine and reduction process require high operating conditions, otherwise the optical purity of the product will not be high; the route three uses m-trifluoromethyl Phenylpropionic acid instead of m-trifluoromethylphenylpropanal (Wang,X.,Chen,Y.,Crockett,R.,et al.Synthesis of cinacalcet congeners[J].Tetrahedron Lett.,2004,8355 -8358.), in comparison, it is easier to obtain, and the preparation yield of the following amide is also high. During the reduction process, it is not easy to affect the optical purity of the product. The disadvantage is that a stronger reducing agent boron is used in the reduction process. Alkanes, although in-situ generation can reduce a lot of danger, but the use of boron trifluoride has brought a lot of inconvenience in operation; route four is to reduce the acid and aldehyde to alcohol, and then derive it into halide or sulfonate and amine A nucleophilic substitution reaction occurs, which reduces the problems caused by the subsequent reduction. At the same time, the nucleophilic substitution brings the problem of secondary substitution by-products and low yield (Turner, K., A review of U.S. patents in the field of organic process development published during June and July 2007. Org. Process Res. Dev., 2007, 11, 940-950)

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