Novel process for early sacubitril intermediates

A compound and nitrogen protection technology, applied in the direction of organic chemical methods, chemical instruments and methods, preparation of organic compounds, etc., can solve the problems of potential danger, expensive catalyst stereoselectivity, etc., and achieve high stereoselectivity effect

Active Publication Date: 2019-03-01
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] However, these methods still have disadvantages such as potentially hazardous reactants or the use of expensive catalysts and / or limited stereoselectivity

Method used

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  • Novel process for early sacubitril intermediates
  • Novel process for early sacubitril intermediates
  • Novel process for early sacubitril intermediates

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Experimental program
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Embodiment

[0135] Where necessary, the following sections describe in more detail individual method steps as set forth above or as delineated in the claims.

[0136] In a first aspect, the present invention relates to a compound of formula (II) or a salt thereof

[0137]

[0138] wherein R1 is a hydrogen or nitrogen protecting group.

[0139] In one embodiment thereof, the compound has formula (II-a) or a salt thereof

[0140]

[0141] wherein R1 is a hydrogen or nitrogen protecting group.

[0142] In one embodiment, R1 is hydrogen.

[0143] In another embodiment, R1 is a nitrogen protecting group selected from: C 1 -C 6 -Alkyl, which is unsubstituted or replaced by three-C 1 -C 6 -Alkylsilyl C 1 -C 7 -alkoxy monosubstituted, disubstituted, or trisubstituted; C 6 -C 10 -aryl; or a heterocyclic group having 5 to 14 ring atoms and 1 to 4 ring atoms independently selected from N, O, S, S(O) or S(O) 2 A monocyclic, bicyclic or tricyclic ring system of heteroatoms; wherein th...

example 3

[0310] Example 3: (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamate 6 manufacturing

[0311] 10% Pd / C (type 10R39, Johnson Matthey; 40% dry weight loading, 30 mg dry weight, moisture corrected to about 50%) and (S)-tert-butyl (1-([1,1 A suspension of '-biphenyl]-4-yl)-3-hydroxy-1-oxopropan-2-yl)carbamate 9 in ethyl acetate (3 mL) was heated at 25 °C under hydrogen (3 bar pressure) for 18 h. Product 6 was isolated by filtration and purified by chromatography if necessary.

[0312] 1 H-NMR (400MHz, DMSO-d6): δ2.30(d,4H),3.14(m,2H),3.73(s,3H),4.39(t,1H),7.32(m,2H),7.38( m,1H),7.44-7.52(m,2H),7.63-7.71(m,4H),8.41(br.s,3H); MS(ES-API): positive ion mode 256.2[M+H] + .

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Abstract

The invention relates to a novel enantioselective process for producing useful intermediates for the manufacture of NEP inhibitors or prodrugs thereof, in particular NEP inhibitors comprising a gamma-amino-delta-biphenyl-alpha-methylalkanoic acid, or acid ester, backbone.

Description

technical field [0001] The present invention relates to a new chemical synthesis route for intermediates used in the preparation of neprilysin (NEP) inhibitors and their prodrugs, especially for the NEP inhibitor prodrug sacubitril ). Background technique [0002] NEP inhibitor prodrug sacabutri (N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methyl Ethyl butyrate; IUPAC name 4-{[(1S,3R)-1-([1,1'-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4 -Oxobutyl]amino}-4-oxobutanoic acid, also known as AHU377) is represented by the following formula (A) [0003] [0004] Together with valsartan, a known angiotensin receptor blocker (ARB), sacabutril forms a sodium salt hydrate complex known as LCZ696, which contains the corresponding Anionic forms of sacabutril and valsartan, sodium cations and water molecules in a molar ratio of 1:1:3:2.5 (the ratio in the asymmetric unit cell of the solid crystal is 6:6:18:15) (WO2007 / 056546), and it exists schematically as for...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C269/06C07C271/18
CPCC07C269/06C07C271/18C07C271/16C07B51/00C07B2200/07C07C215/28C07C225/16C07C229/10C07D265/28
Inventor F·K·克伦贝克-莱尼克T·卡普菲尔
Owner NOVARTIS AG
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