Industrial process and high-purity product for the preparation of (1S,2E)-3-[(1R,2R,3S,5R)-2-[(2Z)-7-(ethylamino)-7-oxohept-2-en-1-yl]-3,5-dihydroxycyclopentyl]-1-(2-phenylethyl)prop-2-en-1-yl 6-(nitrooxy)hexanoate

JP2025523301A5Pending Publication Date: 2026-07-13NICOX SA
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Patent Information

Application Number
JP2025500141
Authority / Receiving Office
JP · JP
Patent Type
Applications
Current Assignee / Owner
Priority Date
2022-07-07
Filing Date
2023-07-06
Publication Date
2026-07-13

AI Technical Summary

Technical Problem

Existing methods for producing hexanoic acid, 6-(nitrooxy)-, (1S,2E)-3-[(1R,2R,3S,5R)-2-[(2Z)-7-(ethylamino)-7-oxo-2-hepten-1-yl]-3,5-dihydroxycyclopentyl]-1-(2-phenylethyl)-2-propen-1-yl ester suffer from low yield and high impurity levels, particularly the 15-(6-chlorohexanoyl) ester of bimatoprost, making large-scale production costly and inefficient.

Method used

A one-pot reaction followed by normal-phase gravity silica gel column chromatography and silica gel filtration is employed to purify the compound, effectively removing impurities and achieving high purity and yield.

Benefits of technology

The method achieves a high-purity compound with less than 0.20% total impurities, specifically less than 0.10% for the 15-(6-chlorohexanoyl) ester, suitable for industrial-scale production of pharmaceutical-grade hexanoic acid, reducing costs and improving efficiency.

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Abstract

The present invention relates to a method for preparing the compound (I) of hexanoic acid, 6-(nitrooxy)-, (1S,2E)-3-[(1R,2R,3S,5R)-2-[(2Z)-7-(ethylamino)-7-oxo-2-hepten-1-yl]-3,5-dihydroxycyclopentyl]-1-(2-phenylethyl)-2-propen-1-yl ester. According to the present invention, the pharmaceutical-grade compound (I) can be efficiently prepared by an esterification of 15-OH bimatoprost by coupling bimatoprost phenyl-boronate with 6-(nitrooxy)hexanoic acid and a one-pot reaction preparation process including removal of the boronate ester protecting group, and a subsequent efficient purification process. The present invention also refers to a high-purity compound (I) substantially free of the impurity 15-(6-chlorohexanoyl) ester of bimatoprost, and an ophthalmic pharmaceutical preparation containing the high-purity compound.
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