[reaction: see text] A practical, large-scale synthesis of a beta-amino ester 1 was developed. A chiral imine derived from (S)-phenylglycinol and 3-trimethylsilylpropanal was coupled with the Reformatsky reagent 3 with high diastereoselectivity (de > 98%) to give (SS)-4a as the major isomer. The amino alcohol residue of the coupling product 4 was oxidatively cleaved with sodium periodate in the presence of methylamine. An unusual selective oxidative cleavage of the (SS)-isomer was observed and the imine 6 was obtained with ee > 99% while the (RS)-4b isomer was not cleaved. Reaction with p-toluenesulfonic acid monohydrate allowed for the hydrolysis of the imine and the isolation of the amine as its salt. The title compound 1 was then obtained by transesterification, desilylation, and hydrochloride salt formation in a one-pot process. The method was successfully applied toward the synthesis of a wide variety of beta-amino esters.
The large-scale preparation of the β-alkynyl β-amino acid
ester
(±)-1,1-dimethylethyl
3-amino-5-(trimethylsilyl)-4-pentynoate
(A) is discussed. It was discovered that addition of a
catalytic
amount of lithium bis(trimethylsilyl)amide (LHMDS) to
a
mixture of tert-butyl acetate and
N,3-bis(trimethylsilyl)-2-propyn-1-imine (B) initiated a self-perpetuating reaction
and
gave high yields of the β-amino ester A upon quench.
This
one-pot procedure eliminated the need to prepare the
unstable
lithium tert-butyl acetate in a separate reactor and enabled
the
reaction to be scaled up and run at a more acceptable
process
temperature (−20 °C) compared to the analogous two-pot
reaction (−45 °C). Addition of 3-(trimethylsilyl)-2-propynal
to
LHMDS in THF at −20 °C followed by
chlorotrimethylsilane
formed the imine B
in situ.
tert-Butyl acetate (6 equiv) was
added followed by a substoichiometric quantity
(0.15−0.20
equiv) of LHMDS. After quenching with aqueous
ammonium
chloride the product A was obtained in a yield averaging
70%.
One-Pot Process for the Preparation of a β-Alkynyl β-Amino Acid Ester.-A large-scale, one-pot method for the synthesis of the racemic title compound (III) is developed. -(BOYS, M. L.; CAIN-JANICKI, K. J.; DOUBLEDAY, W. W.; FARID, P. N.; KAR, M.; NUGENT, S. T.; BEHLING, J. R.; PILIPAUSKAS, D. R.; Org. Process Res.
SC-56525 is a nanomolar inhibitor of plasma renin activity in human, cynomolgus monkey, dog, guinea pig, Yucatan micropig, and rabbit but is less active in rat. The oral bioavailability of SC-56525 in conscious dogs at doses of 5 mg/kg IV and 30 mg/kg PO was 66.1 +/- 16.4%. Oral dosing with SC-56525 at 3, 10, and 30 mg/kg in salt-depleted dogs induced a dose-dependent reduction in mean arterial pressure and inhibition of plasma renin activity with no significant effect on heart rate. In two-kidney, one clip renal hypertensive dogs, SC-56525 given orally at 10, 30, and 60 mg/kg daily for 4 days lowered blood pressure significantly. In conscious dogs monitored in their home cages via radiotelemetry, no significant changes in heart rate occurred in response to large drops in blood pressure in both renal hypertensive and salt-depleted dogs with the renin inhibitor SC-56525. SC-56525 is a nanomolar, orally active inhibitor of renin and effectively lowers blood pressure in both salt-depleted and renal hypertensive dogs.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.