US 5,290,946 AGranted

Processes for the synthesis of 3-(substituted indolyl-2-yl)propenaldehydes

AssigneeSandoz Ltd.

InventorsGeorge T. Lee, Prasad K. Kapa, Oljan Repic

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Abstract

A process for synthesizing compounds of the formula ##STR1## utilizing, as intermediates, oxalyl chloride or bromide and compounds of the formulae R.sub.1 R.sub.2 N--CHO and CH.sub.2 .dbd.CH--O--R.sub.10 are processes for synthesizing compounds of the formula ##STR2## utilizing, as intermediates, compounds of Formula I wherein R.sub.1 is phenyl or substituted phenyl or intermediates in the synthesis of the compounds of formula I which intermediates have the formula ##STR3## wherein R.sub.1 is C.sub.1-3 alkyl, phenyl or phenyl substituted by 1 to 3 substituents each of which is independently C.sub.1-3 alkyl, C.sub.1-3 alkoxy, fluoro, chloro, bromo or nitro (maximum of two nitro groups), R.sub.2 is C.sub.1-3 alkyl, R.sub.10 is C.sub.1-6 alkyl, X.sup..crclbar. is chloride or bromide, and R.sub.3 -R.sub.6 are as defined in the specification. The compounds of Formula II are intermediates in the synthesis of known HMB-CoA reductase inhibitors which inhibit the biosynthesis of cholesterol and are useful as antihyperchloesterolemic agents.

Claims8

Dependent claims

A process for synthesizing a compound of the formula ##STR66## comprising the steps of (i) reacting a compound of the formula ##STR67## with a compound of the formula

POX.sub.3, X--CO--CO--X, X--CO--X or R.sub.11 --SO.sub.2 --X
in an inert anhydrous organic medium to form the corresponding compound of the formula ##STR68## (ii) reacting said compound of the formula ##STR69## with a compound of the formula ##STR70## in an inert anhydrous organic medium to form the corresponding compound of the formula ##STR71## (iii) hydrolyzing said compound of the formula ##STR72## to obtain the corresponding compound of the formula ##STR73## wherein R.sub.1b is phenyl or phenyl substituted by 1 to 3 substituents each of which is independently C.sub.1-3 alkyl, C.sub.1-3 alkoxy, fluoro, chloro, bromo or nitro (maximum of two nitro groups),
R.sub.2 is C.sub.1-3 alkyl,
one of R.sub.3 and R.sub.4 is ##STR74## and the other is primary or secondary C.sub.1-6 alkyl not containing an asymmetric carbon atom, C.sub.3-6 cycloalkyl or phenyl-(CH.sub.2).sub.m --,
wherein R.sub.7 is hydrogen, C.sub.1-3 alkyl, n-butyl, i-butyl, t-butyl, C.sub.1-3 alkoxy, n-butoxy, t-butyl, C.sub.1-3 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,
R.sub.8 is hydrogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,
R.sub.9 is hydrogen, C.sub.1-2 alkyl, C.sub.1-2 alkoxy, fluoro or chloro, and
m is 1, 2 or 3, with the provisos that not more than one of R.sub.7 and R.sub.8 is trifluoromethyl, not more than one of R.sub.7 and R.sub.8 is phenoxy, and not more than one of R.sub.7 and R.sub.8 is benzyloxy,
R.sub.5 is hydrogen, C.sub.1-3 alkyl, n-butyl, i-butyl, t-butyl, C.sub.3-6 cycloalkyl, C.sub.1-3 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, and
R.sub.6 is hydrogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the provisos that not more than one of R.sub.5 and R.sub.6 is trifluoromethyl, not more than one of R.sub.5 and R.sub.6 is phenoxy, and not more than one of R.sub.5 and R.sub.6 is benzyloxy,
R.sub.11 is C.sub.1-6 alkyl, phenyl or 4-methylphenyl, each X is chloro or bromo, and
A.sup..crclbar. is .sup.63 PO.sub.2 X.sub.2 when a compound of the formula POX.sub.3 is utilized in Step (i), X.sup..crclbar. when a compound of the formula X--CO--CO--X or X--CO--X is utilized in Step (i) and R.sub.11 --SO.sub.3.sup..crclbar. when a compound of the formula R.sub.11 -SO.sub.2 --X is utilized in Step (i), wherein X.sup..crclbar. is chloride or bromide.

9 more elements

A process for synthesizing a compound of the formula ##STR80## comprising the steps of (i) reacting a compound of the formula ##STR81## with a compound of the formula

X--CO--CO--X
to form the corresponding compound of the formula ##STR82## (ii) reacting said compound of the formula ##STR83## with a compound of the formula ##STR84## to form the corresponding compound of the formula ##STR85## (iii) reacting said compound of the formula ##STR86## with a compound of the formula ##STR87## in the presence of a scavenger for the compound of the formula R.sub.10 --OH that is formed in the reaction to form the corresponding compound of the formula ##STR88## (iv) hydrolyzing said compound of the formula ##STR89## to obtain the corresponding compound of the formula ##STR90## wherein R.sub.1 is C.sub.1-3 alkyl, phenyl or phenyl substituted by 1 to 3 substituents each of which is independently C.sub.1-3 alkyl, C.sub.1-3 alkoxy, fluoro, chloro, bromo or nitro (maximum of two nitro groups),
R.sub.2 is C.sub.1-3 alkyl
one or R.sub.3 and R.sub.4 is ##STR91## and the other is primary or secondary C.sub.1-6 alkyl not containing an asymmetric carbon atom, C.sub.3-6 cycloalkyl or phenyl-(CH.sub.2).sub.m --,
wherein R.sub.7 is hydrogen, C.sub.1-3 alkyl, n-butyl, i-butyl, t-butyl, C.sub.1-3 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,
R.sub.8 is hydrogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,
R.sub.9 is hydrogen, C.sub.1-2 alkyl, C.sub.1-2 alkoxy, fluoro or chloro, and
m is 1, 2 or 3, with the provisos that not more than one of R.sub.7 and R.sub.8 is trifluoromethyl, not more than one of R.sub.7 and R.sub.8 is phenoxy, and not more than one of R.sub.7 and R.sub.8 is benzyloxy,
R.sub.5 is hydrogen, C.sub.1-3 alkyl, n-butyl, i-butyl, t-butyl, C3-6cycloalkyl, C.sub.1-3 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, and
R.sub.6 is hydrogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the provisos that not more than one of R.sub.5 and R.sub.6 is trifluoromethyl, not more than one of R.sub.5 and R.sub.6 is phenoxy, and not more than one of R.sub.5 and R.sub.6 is benzyloxy, R.sub.10 is C.sub.1-6 alkyl,
each X is chloro or bromo and
each X.sup..crclbar. is chloride or bromide.

9 more elements

Dependencies are inferred from the claim text.

Facts

Application: 07/980,055Filed 23 Nov 1992 · continuation
Priority: 13 Oct 1988
Granted: 1 Mar 1994
Term ends: Not estimatedThe source records don’t support an estimate.

Classification8 codes

C07D 233/64
Having two double bonds between ring members or between ring members and non-ring members: with substituted hydrocarbon radicals attached to ring…
C07C 51/367
By reactions not involving formation of carboxyl groups: by introduction of functional groups containing oxygen only in singly bound form
C07C 59/48
Containing hydroxy or O-metal groups: containing six-membered aromatic rings
C07C 223/02
Compounds containing amino and —CHO groups bound to the same carbon skeleton: having amino groups bound to acyclic carbon atoms of the carbon skeleton

Family

Serial257,475Parent of this continuation-in-part · filed 13 Oct 1988
Serial348,548Parent of this continuation-in-part · filed 8 May 1989
Serial402,947Parent of this continuation · filed 5 Sep 1989
Serial631,576Parent of this continuation-in-part · filed 21 Dec 1990
Serial661,286Parent of this division · filed 26 Feb 1991
Serial890,492Parent of this continuation · filed 28 May 1992
US 5,118,853 AParent of this division
US 5,290,946 AThis patent

From the US filing history. Foreign family members aren’t listed.