DESC:Field of the Invention

The specification discloses an improved process for the preparation of Sacubitril Intermediates, e.g. N-[(1R)-5-[1,1'-biphenyl]-4-yl-4-tert-butoxycarbonylaminopent-2-enoic acid ethyl ester or its salts thereof (referred herein after “ethyl ester intermediate”).

Background of the invention

Sacubitril is an antihypertensive drug used in combination with Valsartan. The combination is marketed under the brand name, Entresto by Novartis, is a treatment for heart failure. Sacubitril is chemically known as 4-{[(2S,4R)-1-(4-biphenylyl)-5-ethoxy-4-methyl-5-oxo-2-pentanyl] amino}-4-oxobutanoic acid, compound of Formula I

Formula-I

US Patent No. 5,217,996 and US 5,354,892 describe Sacubitril or pharmaceutically acceptable salt thereof and its process for preparation.

Other processes for the preparation of Sacubitril are also disclosed in various Patent/ application No. US9085529; US8946481; US8263629; US 9006249; US 8835668; US9061973; US 9181175; US8703990; US20150274650; US20140142320; US20150274642; US20150166468; US20150210632; US20090326066; US20130172572; CN 104557600 ; CN104860894 and CN 10500117.

Summary of the Invention

One embodiment discloses an improved process of preparation of N-[(1R)-5-[1,1'-biphenyl]-4-yl-4-tert-butoxycarbonylaminopent-2-enoic acid ethyl ester or its salts thereof, compound of Formula II,

Formula II
the process comprises the step of
a) reacting N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamic acid 1,1-dimethylethyl ester with suitable oxidizing agent in presence of suitable buffer in suitable solvent to obtain N-[(1R)-2-[1,1'-]-4-yl-1-(formyl)ethyl]carbamic acid 1,1-dimethylethyl ester,
b) condensing N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(formyl)ethyl]carbamic acid 1,1-dimethylethyl ester with (carbethoxyethylidene)triphenylphosphorane in presence of complexing agent in suitable solvent to obtain N-[(1R)-5-[1,1'-biphenyl]-4-yl-4-tert-butoxycarbonylaminopent-2-enoic acid ethyl ester

Another embodiment discloses N-[(1R)-5-[1,1'-biphenyl]-4-yl-4-tert-butoxycarbonylaminopent-2-enoic acid ethyl ester or its salts thereof, having purity more than 98 % when measured by HPLC.

Description of the Invention

For purposes of the present invention, the following terms are defined below.

The Sacubitril and its intermediates of the invention may be prepared/used as free bases or as salt.

The pharmaceutically acceptable salt or salts refers to salts is selected from the group comprising alkali metal salts and alkaline-earth metal salts, wherein alkali metal salts is selected from sodium, lithium, potassium salts and alkaline-earth metal salts selected from calcium, magnesium salts and ammonium salts.

One embodiment, discloses an improved process of preparation of N-[(1R)-5-[1,1'-biphenyl]-4-yl-4-tert-butoxycarbonylaminopent-2-enoic acid ethyl ester or its salts thereof, compound of Formula II,

Formula II
the process comprises the step of
a) reacting N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamic acid 1,1-dimethylethyl ester with suitable oxidizing agent in presence of suitable buffer in suitable solvent to obtain N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(formyl)ethyl]carbamic acid 1,1-dimethylethyl ester,
b) condensing N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(formyl)ethyl]carbamic acid 1,1-dimethylethyl ester with (carbethoxyethylidene)triphenylphosphorane in presence of complexing agent in suitable solvent to obtain N-[(1R)-5-[1,1'-biphenyl]-4-yl-4-tert-butoxycarbonylaminopent-2-enoic acid ethyl ester

The process involves suspending of suitable oxidizing agent in presence of suitable buffer in suitable solvent, followed by slowly addition of solution of N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl) ethyl] carbamic acid 1,1-dimethylethyl ester in suitable solvent, wherein the suitable solvent may be one or more of halogenated solvent, alcoholic solvent, ketone solvent, water or mixtures thereof. The halogenated solvent is selected from dichloromethane, dichloroethane or chloroform; alcoholic solvent is selected from methanol, ethanol, isopropanol, n-propanol, butanol, isobutanol or propylene glycol; ketone solvents is selected from acetone, methyl ethyl ketone, methyl isobutyl ketone or methyl tert-butyl ketone; ether is selected from diethyl ether, methyl tert-butyl ether, tetrahydrofuran or diisopropyl ether.

The suitable oxidizing agent may be one or more of peroxides; alkali or alkaline peroxides; peracids; hypohalite; perborates; N-oxides; permanganates; chromium compounds; ozone or oxygen. The peroxides is selected from hydrogen peroxide, alkali or alkaline peroxides is selected from sodium peroxide; peracids is selected from peracetic acid, m-chloro perbenzoic acid, trifluoro peracetic acid, 2,4-dinitroperbenzoic acid, oxone or persulfuric acid; hypohalite is selected from sodium hypochlorite or sodium hypobromite; perborates is selected from sodium perborate; N-oxides is selected from pyridine-N-oxide or N-methylmorpholine-N-oxide; permanganates is selected from sodium permanganate or potassium permanganate; chromium compounds is selected from chromium trioxide, pyridinium chlorochromate, pyridinium dichromate, collins reagent, Jones reagent or Sarett reagent.

The suitable buffer may be one or more of sodium acetate, sodium bicarbonate, sodium carbonate, potassium acetate, potassium carbonate or potassium bicarbonate.

Reaction mixture is stirred at temperature of about 25°C to 35 °C for the period of 30 minute. After completion of the reaction, (carbethoxyethylidene)triphenylphosphorane is added to the reaction mixture containing N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(formyl)ethyl]carbamic acid 1,1-dimethylethyl ester, (at temperature of about 25°C to 35 °C. The reaction mixture is further stirred at temperature of about 25°C to 35 °C for 2 hours. Reaction mixture is filtered over celite and washed with dichloromethane. The complexing agent is added to filtrate, wherein complexing agent may be one or more of ethylenediaminedisuccinic acid, disodium dihydrogen ethylenediaminetetraacetate or nitrilotriacetic acid; Silica based scavengers SiliaMetS TAAcOH, SiliaMetS TAAcONa, SiliaMetS Cysteine, SiliaMetS Imidazole or SiliaMetS Triamine and stirred for about 24 hours to get N-[(1R)-5-[1,1'-biphenyl]-4-yl-4-tert-butoxycarbonylaminopent-2-enoic acid ethyl ester.

In one another embodiment process of compound of Formula II is schematically presented in the following scheme 1:

Another embodiment discloses N-[(1R)-5-[1,1'-biphenyl]-4-yl-4-tert-butoxycarbonylaminopent-2-enoic acid ethyl ester or its salts thereof having purity more than 98 % when measured by HPLC.

The compound of Formula-II or a salt thereof can be converted to sacubitril of Formula-I or pharmaceutically acceptable salts according to method described in US 5,217,996.

The embodiments of the specification are further illustrated by way of following examples, which do not limit the scope of the claims. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the claims.

EXAMPLES

Example 1: Preparation of N-[(1R)-5-[1,1'-biphenyl]-4-yl-4-tert-butoxycarbonylaminopent-2-enoic acid ethyl ester
A reaction flask was charged with pyridinium chlorochromate (79 gm; 0.366 moles) and sodium acetate (30 gm; 0.366 moles) in dichloromethane (1.5 L) followed by slow addition of solution of N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamic acid 1,1-dimethylethyl ester(100 gm; 0.305 moles) in dichloromethane (500 mL). Reaction mixture was stirred at temperature of 25-35°C for 30 minutes. After completion of the reaction, (carbethoxyethylidene)triphenylphosphorane (110.5 gm; 0.305 moles) was added to the reaction mixture containing N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(formyl)ethyl]carbamic acid 1,1-dimethylethyl ester added and reaction mixture was stirred at temperature 25-35 °C for the period 2 hours. Reaction mixture was then filtered over celite and washed with dichloromethane (2x200 mL). Charged ethylenediaminetetraacetic acid (EDTA) (2 gm) to the obtained filtrate, and stirred for another 24 hrs. Reaction mixture was then filtered through 0.5 micron membrane filter and washed with water (1000 mL), the organic layer was extracted and preserved. The aqueous layer was again washed with dichloromethane (200 mL), the organic layer was extracted and, aqueous layer was discarded. Both the organic layers were combined and washed with 1M aqueous sodium hydroxide solution, the organic layer was again extracted and washed with saturated NaCl solution, aqueous layer discarded The Organic layer was concentrated under vacuum to get thick oily mass which was then purified by column chromatography using ethyl acetate/hexane to get the titled compound.
Yield: 68.0 gm
HPLC Purity: >99 %
,CLAIMS:1. An improved process of preparation of N-[(1R)-5-[1,1'-biphenyl]-4-yl-4-tert-butoxycarbonyl amino pent-2-enoic acid ethyl ester or its salts thereof, compound of Formula II,

Formula II
the process comprises the step of
a) reacting N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamic acid 1,1-dimethylethyl ester with suitable oxidizing agent in presence of suitable buffer in suitable solvent to obtain N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(formyl)ethyl]carbamic acid 1,1-dimethylethyl ester; and
b) condensing N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(formyl)ethyl]carbamic acid 1,1-dimethylethyl ester with (carbethoxyethylidene)triphenylphosphorane in presence of complexing agent in suitable solvent to obtain N-[(1R)-5-[1,1'-biphenyl]-4-yl-4-tert-butoxycarbonylaminopent-2-enoic acid ethyl ester.

2. The process of claim 1, wherein suitable solvent is selected from one or more of halogenated solvent, alcoholic solvent, ketone solvent, water or mixtures thereof.

3. The process of claim 1, wherein suitable buffer is selected from one or more of sodium acetate, sodium bicarbonate, sodium carbonate, potassium acetate, potassium carbonate, or potassium bicarbonate.

4. The process of claim 1, wherein suitable oxidizing agent is selected from one or more of peroxides; alkali or alkaline peroxides; peracids; hypohalite; perborates; N-oxides; permanganates; chromium compounds; ozone or oxygen.

5. The process of claim 1, wherein complexing agent is selected from one or more of ethylenediaminetetraacetic acid (EDTA), ethylenediaminedisuccinic acid, disodium dihydrogen ethylenediaminetetraacetate or nitrilotriacetic acid; Silica based scavengers: Silia MetS TAAcOH, SiliaMetS TAAcONa, SiliaMetS Cysteine, SiliaMetS Imidazole or SiliaMetS Triamine.

6. The process of claim 1, wherein compound of formula-II has purity more than 99%, when measured by HPLC.

7. The process of claim 1, wherein step (a) and (b) are carried out in one pot process.

8. The process of claim 1, wherein step (a) and (b) are carried out at temperature of about 25-35 °C.

9. The process of claim 1, wherein compound of formula-II is converted to sacubitril or pharmaceutically acceptable salt thereof.