Preparation method for paricalcitol

Abstract

The invention discloses a preparation method for paricalcitol. The preparation method comprises the following steps: (1) subjecting a compound 1 to a hydrolysis reaction so as to prepare a compound 2;(2) subjecting the compound 2 to oxidation with Dess-Martin periodinane so as to prepare a compound 3; (3) subjecting the compound 3 to a reaction with a compound 4 so as to prepare a compound 5; and(4) subjecting the compound 5 to hydrolysis so as to prepare a crude paricalcitol product. Accordinccording to the method of the invention, the content of an epimer impurity B in the crude paricalcitol product is reduced from the source by selecting appropriate reaction conditions, and subsequent purification steps for paricalcitol are simplified; and the preparation method has high yield and little impurities, and is more suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a method for preparing paricalcitol suitable for industrial production. Background technique [0002] Paricalcitol (Paricalcitol, chemical name: 19-nor)-1α, 3β, 25-trihydroxy-9, 10-secoergosta-5(Z), 7(Z), 22(E)-tri 19-nor-1,25-dihydroxyvitamin D2) is a synthetic, bioactive vitamin D analogue of calcitriol, whose side chain (D2) and A(19-des A) The ring was modified. Paricalcitol inhibits the secretion of parathyroid hormone (PTH) by binding to vitamin D receptors (D.M.Robinson, L.J.Scott, Drugs, 2005, 65(4), 559-576), is used for the prevention and treatment of secondary A drug for onset hyperparathyroidism (SHPT), which has shown preventive and curative effects on SHPT in stage III and IV chronic kidney disease (CKD) patients undergoing dialysis and transplantation, and has become the most widely used drug for dialysis patients Drugs for the prevention and treatment of SHPT...

AI Technical Summary

Problems solved by technology

[0009] (1) Paricalcitol contains isomers of multiple configurations, and its synthetic intermediate fragment 1 and intermediate 3 will all produce epimerization, resulting in a large amount of impurities. US5281731, US5086191 and existing documents all no research on this

[0010] (2) In US5281731 and US5086191, two patents use HPLC to separate isomers and purify the final compound, but Paricalcitol is very polar, and the structure of the isomer impurities in the reaction product is similar to that of Paricalcitol Highly similar structures make HPLC difficult to purify, and HPLC as a preparative method is generally not suitable for industrial scale applications

[0011] (3) The productive rate of preparing Paricalcitol is not disclosed in US5086191

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