Process for preparation of optically pure and optionally substituted 2-(1-hydroxy-alkyl)-chromen-4-one derivatives and their use in preparing pharmaceuticals

Patent metadata

Field	Value
Publication number	US-11478481-B2
Application number	US-201816156378-A
Country	US
Kind code	B2
Filing date	Oct 10, 2018
Priority date	May 4, 2012
Publication date	Oct 25, 2022
Grant date	Oct 25, 2022

Abstract

The present invention relates to compounds useful as pharmaceutical intermediates, to processes for preparing the intermediates, to intermediates used in the processes, and to the use of the intermediates in the preparation of pharmaceuticals. In particular, the present invention concerns enantiomerically pure optionally substituted 2-(1-hydroxy-alkyl)-chromen-4-one derivatives represented by formula (IA) and (IB), processes for preparing the alcohol derivatives and their use in preparing pharmaceuticals.

First claim

The invention claimed is:

1. A process for preparing a PI3K inhibitor of formula (I)

or a tautomer thereof, N-oxide thereof, pharmaceutically acceptable ester thereof, prodrug thereof, or pharmaceutically acceptable salt thereof, wherein
each occurrence of R is independently selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, —COOR x , —C(O)R x , —C(S)R x , —C(O)NR x R y , —C(O)ONR x R y , —NR x R y , —NR x CONR x R y , —N(R x )SOR x , —N(R x )SO 2 R y , —NR x C(O)OR y , —NR x C(O)R y , —NR x C(S)R y , —NR x C(S)NR x R y , —SONR x R y , —SO 2 NR x R y , —OR x , —OR x C(O)NR x R y , —OR x C(O)OR x , —OC(O)R x , —OC(O)NR x R y , —R x NR y C(O)R z , —R x OR y , —R x C(O)OR y , —R x C(O)NR x R y , —R x C(O)R y , —R x OC(O)R y , —SR x , —SOR x , —SO 2 R x , and —ONO 2 , wherein each occurrence of R x , R y and R z is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or (i) any two of R x and R y , when bound to a common atom, are joined to form a substituted or unsubstituted, saturated or unsaturated 3-14 membered ring, which may optionally include heteroatoms which may be the same or different and are selected from O, NR z or S, or (ii) any two of R x and R y , when bound to a common atom, are joined to form an oxo (═O), thio (═S) or imino (═NR f ) (wherein R f is hydrogen or substituted or unsubstituted alkyl);
R 1 is substituted or unsubstituted C 1-6 alkyl;
Cy 1 is a monocyclic or bicyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
n is an integer selected from 0, 1, 2, 3 or 4;
Cy 2 is selected from a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
L 1 is absent;
each occurrence of R a and R b may be the same or different and are independently selected from hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted (C 1-6 )alkyl, —NR c R d (wherein R c and R d are independently hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted (C 1-6 )alkyl, or (C 1-6 )alkoxy) and —OR c (wherein R c is substituted or unsubstituted (C 1-6 )alkyl) or when R a and R b are directly bound to a common atom, they may be joined to form an oxo group (═O) or form a substituted or unsubstituted, saturated or unsaturated 3-10 member ring (including the common atom to which R a and R b are directly bound), which may optionally include one or more heteroatoms which may be the same or different and are selected from O, NR d (wherein R d is hydrogen or substituted or unsubstituted (C 1-6 )alkyl) or S;
Y is selected from 0, S, and NR a ; and
q is 0, 1 or 2,

the process comprising
(a) treating a compound of formula (IA)

where variables R, n, Cy 1 , and R 1 are as defined above, with Cy 2 -H to give the desired compound of formula (I) or a tautomer thereof, N-oxide thereof, pharmaceutically acceptable ester thereof, prodrug thereof, or pharmaceutically acceptable salt thereof; and
(b) optionally converting the compound of formula (I) to a salt of the compound.

2. A process for preparing a PI3K inhibitor of formula (I)

or a tautomer thereof, N-oxide thereof, pharmaceutically acceptable ester thereof, prodrug thereof, or pharmaceutically acceptable salt thereof, wherein
each occurrence of R is independently selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, —COOR x , —C(O)R x , —C(S)R x , —C(O)NR x R y , —C(O)ONR x R y , —NR x R y , —NR x CONR x R y , —N(R x )SOR x , —N(R x )SO 2 R y , —NR x C(O)OR y , —NR x C(O)R y , —NR x C(S)R y , —NR x C(S)NR x R y , —SONR x R y , —SO 2 NR x R y , —OR x , —OR x C(O)NR x R y , —OR x C(O)OR x , —OC(O)R x , —OC(O)NR x R y , —R x NR y C(O)R z , —R x OR y , —R x C(O)OR y , —R x C(O)NR x R y , —R x C(O)R y , —R x OC(O)R y , —SR x , —SOR x , —SO 2 R x , and —ONO 2 , wherein each occurrence of R x , R y and R z is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or (i) any two of R x and R y , when bound to a common atom, are joined to form a substituted or unsubstituted, saturated or unsaturated 3-14 membered ring, which may optionally include heteroatoms which may be the same or different and are selected from O, NR z or S, or (ii) any two of R x and R y , when bound to a common atom, are joined to form an oxo (═O), thio (═S) or imino (═NR f ) (wherein R f is hydrogen or substituted or unsubstituted alkyl);
R 1 is substituted or unsubstituted C 1-6 alkyl;
Cy 1 is a monocyclic or bicyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
n is an integer selected from 0, 1, 2, 3 or 4;
Cy 2 is selected from a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
L 1 is absent;
each occurrence of R a and R b may be the same or different and are independently selected from hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted (C 1-6 )alkyl, —NR c R d (wherein R c and R d are independently hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted (C 1-6 )alkyl, or (C 1-6 )alkoxy) and —OR c (w

Assignees

• Rhizen Pharmaceuticals Sa
• Rhizen Pharmaceuticals Ag

Inventors

• Raman Jayaraman V
• Vakkalanka Swaroop K

Classifications

• C07D487/04

  Ortho-condensed systems · CPC title

• A61K31/5377 Primary

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/52

  Purines, e.g. adenine · CPC title

• C07D473/34

  attached in position 6, e.g. adenine · CPC title

• C07B2200/07

  Optical isomers · CPC title