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NOVEL AMINE SALT OF SACUBITRIL

IP.com Disclosure Number: IPCOM000248549D
Publication Date: 2016-Dec-16
Document File: 6 page(s) / 163K

Publishing Venue

The IP.com Prior Art Database

Related People

Svetoslav S. Bratovanov: AUTHOR [+2]

Abstract

The present disclosure provides a novel 1-adamantylamine salt of Sacubitril and a process for the preparation thereof.

This text was extracted from a PDF file.
This is the abbreviated version, containing approximately 41% of the total text.

NOVEL AMINE SALT OF SACUBITRIL

ABSTRACT

The present disclosure provides a novel 1-adamantylamine salt of Sacubitril and a process for

the preparation thereof.

Sacubitril is the non-proprietary name for 4-{[(1S,3R)-1-([1,1’-biphenyl]-4-ylmethyl)-4-ethoxy-3-

methyl-4-oxobutyl]amino}-4-oxobutanoic acid. Sacubitril, in combination with Valsartan, is marketed in

the United States as ENTRESTO®(1), in the form of a macromolecular complex containing anionic Sacubitril, anionic Valsartan, sodium cations and water molecules in a ratio of 1:1:3:2.5. Sacubitril is a

neprilysin inhibitor and Valsartan is an angiotension II receptor blocker.

(1)

The present disclosure provides a 1-adamantylamine salt of Sacubitril (2), useful in the

preparation of [Sacubitril-Valsartan]Na3•2.5H2O.

O

O

HN

O

O

HONH2 .

(2)

The novel Sacubitril 1-adamantylamine salt of the present disclosure offers an opportunity for

isolation and purification of crude Sacubitril free acid, which is reported to be an oily substance

unsuitable for manipulation. The novel salt described herein is an isolatable and purified form of

Sacubitril, amenable to further processing into other forms as required.

BRIEF DESCRIPTION OF THE DRAWINGS

Embodiments of the present invention are described, by way of example only, with reference

to the attached Figures.

Figure 1 is a Powder X-Ray Diffraction (PXRD) diffractogram of Sacubitril 1-adamantylamine salt as

prepared in Example 3.

DESCRIPTION

In a first aspect, there is provided a novel Sacubitril 1-adamantylamine salt of Formula (2).

Preferably, the Sacubitril 1-adamantylamine salt is crystalline. An illustrative Powder X-Ray Diffraction

(PXRD) diffractogram of Sacubitril 1-adamantylamine salt, as prepared in Example 3, is shown in Figure

1. A peak listing, comprising some peaks from the PXRD diffractogram in Figure 1, and their relative

intensities, is provided in Table 1.

Table 1: Relative peak intensities of Sacubitril 1- adamantylamine salt from Figure 1

Angle (° 2θ) Relative intensity (%) 5.7 24.7 6.8 24.6 8.2 12.0

14.3 62.7 15.5 41.0

Table 1: Relative peak intensities of Sacubitril 1- adamantylamine salt from Figure 1

Angle (° 2θ) Relative intensity (%) 16.3 27.9 16.4 29.4 17.8 25.1 19.7 100.0 21.4 17.7 22.8 13.1

In a second aspect, there is provided a process for the preparation of Sacubitril 1-

adamantylamine salt of Formula (2), the process comprising reaction of Sacubitril, in the presence of a

first crystallization solvent, with 1-adamantylamine to afford a salt of Formula (2).

In the reaction of Sacubitril and 1-adamantylamine, a first crystallization solvent may be

selected from the group consisting of esters, such as isopropyl acetate and ethyl acetate, and aromatic

hydrocarbons such as toluene. A preferred solvent is isopropyl acetate.

An amount of the first crystallization solvent with respect to Sacubitril, expressed in volumes, of

about 5 volumes to about 35 volumes, preferably 15 to 20 volumes may be used. As used herein,

“volumes” refer...