1038924-61-6 Usage
Description
Sacubitril is a neprilysin
inhibitor prodrug developed by Novartis that was approved
as part of an orally administered supramolecular sodium salt
complex with the angiotensin receptor blocker (ARB) valsartan
in the U.S. and EU in 2015. Sacubitril/valsartan (also known
as LCZ-696) is a first-in-class dual angiotensin receptor
blocker neprilysin inhibitor (ARNI) marketed for the treatment
of chronic heart failure with reduced ejection fraction
(HFrEF). It represents a novel mechanistic approach to
targeting HFrEF and is the first pharmacologic agent approved
for HFrEF since 2004. Sacubitril is metabolized by enzymatic
conversion of the ethyl ester to the active diacid (LBQ-657,
structure not disclosed), which inhibits neprilysin and prevents endogenous natriuretic peptide degradation. Neprilysin
inhibitors like sacubitril are not effective as monotherapy and
need to be combined with a reninangiotensin aldosterone
system (RAAS) inhibitor such as valsartan. Notably, dual
neprilysin and angiotensin-converting enzyme (ACE) inhibition,
as in omapatrilat, was found to be associated with an
increased risk of life-threatening angioedema due to increased
bradykinin levels. In phase III clinical trials, sacubitril/
valsartan displayed a superior safety profile to enalapril, with
a 20% decrease in heart failure hospitalizations or cardiovascular
death and a 16% reduction in the risk of death from any
cause. Sacubitril/valsartan is now recommended as the standard
of care for HFrEF as an alternative to ACEs and ARBs.
Synthesis
Several routes to sacubitril, particularly to advanced
intermediates, have been published in the primary and patent
literature.23 They differ generally in their choice of chiral pool
starting material and their approach to introduction of the
second stereocenter. The industrial scale synthesis of
intermediate 47 has been reported. Accordingly, addition of the cuprate of biaryl
bromide 41 to (S)-epichlorohydrin 42 followed by subjection
to HCl provided chloropropanol 43 in 92% yield and 99% ee.
Next, a Mitsunobu reaction involving succinimide 44 followed
by treatment with refluxing HCl and NaOH generated the
corresponding aminoalcohol, which was isolated via crystallization
as the HCl salt prior to Boc protection to give N-Boc
aminoalcohol 45 in >99% ee. Alcohol 45 was then carried
through a four-step process to give acid 47 in 75% yield,
starting with oxidation of the alcohol to the corresponding
aldehyde with TEMPO/NaOCl. The organic phase was carried
forward directly into a Wittig reaction with ylide 46, generating
an α,β-unsaturated ester which was hydrolyzed to acid 47 with
LiOH in an ethanol/water mixture. Interestingly, a separate
patent disclosed the stereoselective hydrogenation of the
trisubstituted olefin 47, in which subjection of 47 to catalytic
[Ru(p-cymene)I2]2 and chiral phosphine ligand Mandyphos
SL-M004-1 (48) under 40 bar of hydrogen gas in warm ethanol
delivered 49 in 99:1 dr before recrystallization.
Subsequently, activation of the acid as the acid halide through
the use of thionyl chloride and ethanol not only reestablished
the ethyl ester but removed the Boc group, revealing a primary
amine which then reacted with succinic anhydride to ultimately
deliver sacubitril (V). The freebase form of sacubitril does not
readily crystallize; the isolation of a number of pharmaceutically acceptable salts of sacubitril via crystallization, most preferably
the calcium salt 50 or sodium salts, have been reported.
Preparation of the sacubitril/valsartan supramolecular complex
(trisodium salt, hemihydrate) has been described on a kilo-scale
from sacubitril calcium salt via neutralization to the freebase
and subsequent complexation with valsartan in iPrOAc/
acetone. Addition of NaOH and crystallization then provided
the desired trisodium salt hemihydrate.
Check Digit Verification of cas no
The CAS Registry Mumber 1038924-61-6 includes 10 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 7 digits, 1,0,3,8,9,2 and 4 respectively; the second part has 2 digits, 6 and 1 respectively.
Calculate Digit Verification of CAS Registry Number 1038924-61:
(9*1)+(8*0)+(7*3)+(6*8)+(5*9)+(4*2)+(3*4)+(2*6)+(1*1)=156
156 % 10 = 6
So 1038924-61-6 is a valid CAS Registry Number.
1038924-61-6Relevant articles and documents
A method for the synthesis of pharmaceutical intermediates
-
Paragraph 0036; 0038; 0060-0061, (2017/11/16)
The invention relates to the field of medical chemistry, particularly the field of pharmaceutical synthesis and more particularly a synthetic method for a pharmaceutical intermediate. The synthetic method comprises the steps: by taking 4-bromobiphenyl as an initial raw material, carrying out reaction with boride to obtain a compound II; and further synthesizing a target compound by directly taking a post-reaction solution as a raw material by treating or not treating a reaction liquid of the compound II. By adopting the synthetic route disclosed by the invention, the production process is simple, the product yield is high, the purification treatment is simple, the product purity is high after simple treatment, and the preparation cost is low, and the synthetic method is suitable for industrial production.
NEPRILYSIN INHIBITORS
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, (2012/06/30)
In one aspect, the invention relates to compounds having the formula: where R1-R6, a, b, and X are as defined in the specification, or a pharmaceutically acceptable salt thereof. These compounds have neprilysin inhibition activity. In another aspect, the invention relates to pharmaceutical compositions comprising such compounds; methods of using such compounds; and processes and intermediates for preparing such compounds.
